Current Drug Targets - CNS & Neurological Disorders, 2005, 4, 361-381361
Molecular Targets and Therapeutic Strategies in Huntington's Disease
A. Cristina Rego*,1 and Luís Pereira de Almeida*,2
1Faculty of Medicine and 2Faculty of Pharmacy, Center for Neuroscience and Cell Biology, University of
Coimbra, Coimbra, Portugal
Abstract: This article provides an overview of the molecular mechanisms associated with striatal neuronal
degeneration in Huntington’s disease (HD), the most studied of the diseases caused by polyglutamine
expansion. We discuss the current status of research in cellular and animal models of HD, in which protein
aggregation, excitotoxicity, mitochondrial dysfunction, transcription deregulation, trophic factor starvation
and the disruption of axonal transport appear to be key features for selective striatal neurodegeneration. We
further emphasize some of the most promising current strategies in HD treatment. We delineate the molecular
and cellular rationale underlying the development of new pharmaceutical interventions that offer new hope of
future treatment for HD patients worldwide.
Keywords: Huntington's disease, huntingtin, CAG, neuronal death, protein aggregates, polyglutamine diseases, trinucleotide
1. REPEAT DISEASES
In the last decade, a new kind of mutation underlying
previously unrelated, inherited neurodegenerative disorders
was unravelled by molecular genetic analysis . In the
human genome there are repetitive sequences of three
nucleotides, once considered benign, that above a certain
number become pathogenic . The members of this family,
called triplet repeat disorders, were first described in 1991
. Since then 15 different representatives have been
described . Moreover, an expansion disease with a larger
repeat unit (CCCCG) has been described . These disorders
are all neurological or neuromuscular and are characterized by
somatic and germline instability of the mutation . From
generation to generation, there is a tendency towards
expansion of the repeat length in paternal transmission. The
increase in the repeat number within generations results in
earlier onset and increased severity of the diseases, a
phenomenon known as anticipation. Simultaneously, an
expansion of repeat number is observed in post-mitotic cells
in some regions. Although the mechanisms that cause the
different diseases remain largely unknown, the repeats may
interfere with DNA structure and transcription leading to
either a loss or a gain of function of the corresponding
transcript . According to the position of the trinucleotide
repeats within the human genes, repeat disorders can be
classified into two groups: a) diseases with repeats in non-
coding sequences and b) diseases with CAG repeats in
coding sequences that transcribe and translate into mutant
proteins with expanded polyglutamine tracts.
Dysfunction and degeneration in different tissues are
observed in diseases with repeats in non-coding sequences.
The sequence that is expanded is variable – CGG, GCC,
GAA, CTG or CAG - as well as its gene location and repeat
numbers. These are generally high, compared to the coding
repeat diseases . The repeat nature, number, and protein
context affect the mechanism of degeneration associated with
In 1991, the group of Kenneth Fischbeck first identified
a polyglutamine repeat as the cause of a genetic neurological
disease - spinal bulbar muscular atrophy (SBMA) . Since
then, the number of diseases identified as polyglutamine
disorders has been increasing  (Table 1). In all these
pathologies, an expansion of CAGs within the coding region
of a gene, specific for each disorder, results in an expansion
of consecutive glutamine residues in the translated protein
(Table 1). The number of repeats is comparatively smaller in
the polyglutamine group of diseases than the diseases with
repeats in non-coding sequences. The age of onset of the
pathology correlates, partly, with the polyglutamine number.
All these polyglutamine diseases present similarities that
suggest some overlap of mechanisms of pathogenesis .
The translated polyglutamine repeats presumably alter the
proteins conformations and the interactions with other
proteins. This leads to neuronal dysfunction, usually in mid-
life which later progresses to neurodegeneration with decline
in motor and cognitive functions. According to some
authors, polyglutamine pathogenesis is not due to the loss
of function but, instead, to a toxicity of the proteins carrying
a polyglutamine expansion leading to a gain of function.
Similarly, an ectopic expression of a polyglutamine tract in
an unrelated mouse gene induces a pathology .
Moreover, loss of function of the androgen receptor does
cause feminisation, but no weakness or motor neuron
degeneration as happens in SBMA .
Notably, although the genes with the polyglutamine
expansions are ubiquitously
neurodegeneration is limited to specific brain areas. The gene
carrying the repeat expansion confers this regional
selectivity. With the exception of SBMA, an X-linked
*Address correspondence to these authors at the 1Center
Neuroscience and Cell Biology and Institute of Biochemistry, Faculty of
Medicine, R. Larga, University of Coimbra, 3004-504 Coimbra, Portugal;
Tel: + 351-239 820190; Fax:
+351-239 822776; E-mail:
2Center for Neuroscience and Cell Biology and Department of
Pharmaceutical Technology, Faculty of Pharmacy, R. Norte, University of
Coimbra, 3000-295 Coimbra, Portugal; Phone: + 351-239 859927; Fax:
+351-239 827126; E-mail: email@example.com
1568-007X/05 $50.00+.00© 2005 Bentham Science Publishers Ltd.
362 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4Rego and Pereira de Almeida
Table 1.Polyglutamine Expansion Diseases
Normal and Pathogenic
Primary target of neuropathology
Dentatorubro-pallidoluysian atrophy (DRPLA)Atrophin 1
Cerebellum (dentate nucleus), red nucleus, globus
pallidus (external segment), subthalamic nucleus
Huntington’s disease (HD)Huntingtin
Caudate nucleus (medium spiny neurons),
putamen, globus pallidus (external segment)
Spinal and bulbar muscular atrophy (SBMA;
Motor neuron in anterior horn cells of the spinal
cord and brainstem
Spinocerebellar ataxia 1 (SCA1)Ataxin 1
Cerebellum, red nucleus, inferior olive, pons,
anterior horn cells and pyramidal tracts
Spinocerebellar ataxia 2 (SCA2)Ataxin 2
Cerebellar Purkinje cells, cytoplasmatic inclusions
Spinocerebellar ataxia 3 (SCA3)Ataxin 3
Cerebellar dentate neurons, basal ganglia, brain
stem, spinal cord
Spinocerebellar ataxia 6 (SCA6) 4-19
Cerebellar Purkinje cells, dentate nucleus,
inferior olive, cytoplasmatic inclusions
Spinocerebellar ataxia 7 (SCA7) Ataxin 7
Cerebellum, brain stem, macula, visual cortex
Spinocerebellar ataxia 17 (SCA17)TATA-binding
Cerebellum, cortex (diffuse atrophy), caudate
and putamen. NII
Adapted from [1,9,10]
recessive disease, all other polyglutamine disorders are
autosomal dominant .
problem solving, irritability and depression are common
. Later, chorea, difficulty with voluntary motor
activities, dysarthria, dysphagia, and cognitive deficits
develop. In late stages, the patients develop severe rigidity
and bradykinesia along with dementia. In juvenile cases
(onset <20 years), the disease progresses faster and
symptoms are more severe with bradykinesia, rigidity,
seizures, and severe dementia, with little or no chorea .
Swallowing difficulties and complications associated with
immobility are generally involved in the cause of death .
Loss of body weight and lack of muscle bulk have been
reported, even though patients have high calorie intake .
Rubinsztein reports a prevalence of 1 in 10 000 in UK
against a lower prevalence of 1 in 1 000 000 in Japanese and
African populations .
The “interesting transcript 15” (IT15), presently known
as the huntingtin gene , contains 67 exons in both mice
and men. Its locus is located between the regions D4S127
and D4S180 on chromosome 4p16.3 spanning over a 200 kb
genomic region, and is transcribed in two RNA differing in
the 3’ terminal untranslated region. The open reading frame
encodes a large protein of 350 kDa without homology to
other proteins .
The CAG expansion codes for a tail of polyglutamines,
which are located in the N-terminal region of the huntingtin
protein, 17 amino acids downstream of the ATG initiator
codon [19,20]. The protein N-terminal is capable of
interacting with several proteins. Adjacent to the
polyglutamine tract, the protein is comprised of a
polyproline tract. Otherwise, the protein is entirely
composed of several HEAT repeats, a motif of 40 amino
acids of largely unknown function, but which may play a
scaffolding role in the formation of particular protein-protein
2. HUNTINGTON’S DISEASE
Huntington’s disease (HD) is the most prevalent
polyglutamine disease. The disorder was named after George
Huntington who, based on the observation of patients from
his father’s practice in Long Island, published in April 1872
at The Medical and Surgical Reporter, a detailed description
of the disease symptoms. More than one century later, in
1993, the mutation in the huntingtin gene causing the
disease was isolated by a multicenter study, organized by the
Hereditary Disease Foundation. This opened the way for a
molecular study of the disease . The last years were
marked by an intensive research on Huntington’s disease,
which has enlightened on some of the mechanisms that may
be involved in the disease pathogenesis. Despite this, there
is currently no treatment able to block the progression of
this devastating disorder.
HD symptoms involve motor, cognitive, and emotional
disturbances [13,14]. Although the disease can manifest at
any age, generally the first signs appear by 35-50 years of
age, progressing inexorably to death, 15-20 years after the
onset. The most common symptoms are uncontrolled and
uncoordinated involuntary dancing–like movements of limbs
and distal and proximal muscles of the trunk, designated as
chorea, memory deficits, affective disturbances, change of
personality, depression and dementia .
In early stages, subtle coordination changes with
clumsiness and difficulty with balance can be observed. In
addition, minor involuntary movements, difficulty in
Molecular Targets and Therapeutic Strategies in Huntington's Disease Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 363
interactions at its C-terminal . The number of CAG
repeats determines the presence or absence of HD, its
severity, and the time of onset, according to an inverse
relationship between CAG repeat number and the age of
As shown in Figure 1, a number of CAG repeats between
8 and 29 CAGs is within the normal range. An intermediate
length, between 29 and 35 polyglutamine residues is non-
phenotypical but prone to instability and expansion. A
number of repeats over 36 is considered pathologic and will
cause the disease [24,25], although between 36 and 40
repeats the penetrance is incomplete [26-28]. The penetrance
is considered incomplete when, at the age of 65, the person
does not present the disorder symptoms . Between 40 and
50 repeats, the disease attacks patients in midlife. A number
of repeats over 60 causes severe juvenile cases of HD, with
an appearance of the symptoms before the age of 20 .
Numbers up to 240 repeats have rarely been identified in HD
patients . It should be noted that the age of onset only
partially correlates with repeat size. Therefore, no accurate
predictions of the age of onset can be made based on the
polyglutamine repeat length [30,31]. It has been suggested
that other factors, such as genetic polymorphisms adjacent to
CAG repeat, may have significant contributions .
The relationship between CAG repeats length and clinical
progression rate is more controversial [33,34]. Some authors
found an inverse correlation between CAG number and the
speed of progression of the disease [35-37]. Others saw no
correlation , although pathological changes in post
mortem tissue were described
polyglutamine length .
The repeats are unstable and length varies both in
somatic tissues and during
transmission is responsible for an increase in polyglutamine
length leading to anticipation, an increase in severity, or a
decrease of age of onset from generation to generation .
Accordingly, paternal transmission is responsible for most
of the juvenile cases [41,42], with a mean advance of 8 years
in successive generations .
HD is an inherited autosomal dominant disorder. This
has suggested that the disease is caused by a gain of function
mechanism. Accordingly, the huntingtin gene upon
mutation (trinucleotide expansion) gains a new toxic
function that is sufficient to cause the disease .
Supporting this gain of function theory, homozygote
patients have been described who develop phenotypes that
are identical to heterozygotes. Moreover, loss of one allele of
the huntingtin gene does not cause HD [43,44].
Nevertheless, loss of the normal huntingtin function, due to
the presence of a single copy of mutant huntingtin, could
contribute to the pathogenesis. Normal huntingtin appears to
have a neuroprotective function, and up-regulate trophic
factor (brain derived neurotrophic factor (BDNF)) support in
the striatum. The effect is lost in the presence of mutant
huntingtin . Therefore, a loss of function mechanism
may also be important in defining HD pathogenesis. Normal
huntingtin appears to be essential for embryogenesis (knock
out mice for huntingtin show early embryonic mortality),
playing an important role in the development of the
forebrain and increasing the survival of adult neurons in the
forebrain . Mutant protein may sequester wild-type
huntingtin and critically alter its normal function due to
increased proteolysis, or to changes of protein-protein
interactions. Therefore, understanding more about the
function(s) of wild-type huntingtin may bring about new
therapeutic perspectives that prevent the blockade of normal
The previously described symptoms that occur in HD
have been correlated with the pathological changes in the
patient’s brain . Accordingly, the motor changes can be
attributed to the disconnection of the neuronal circuitry
between the cortex, striatum, and globus pallidus. The
striatum in humans designates the ensemble of caudate and
putamen, and is the structure first and most extensively
affected by atrophy and neuronal loss in HD. Degeneration
follows an anatomic pattern progressing from dorsal medial
regions to ventral and lateral regions . Within the
striatum, a selective neuronal loss involves γ-aminobutyric
acid (GABA)-ergic medium spiny neurons (enkephalin and
GABA positive) with preservation of large aspiny
cholinergic neurons. Also involved are the sparse medium
spiny neurons containing somatostatin, neuropeptide Y and
neurodegenerative disorders, neuronal death in HD is
accompanied by the development of gliosis. The Vonsattel
to correlate with
Similarly to other
Fig. (1). Representation of the huntingtin gene and the impact of polyglutamine repeat size on the onset of Huntington’s disease. The
huntingtin gene is transcribed and translated into a 350 kDa protein.
364 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4Rego and Pereira de Almeida
scale, a semi-quantitative scale, is commonly used to grade
the severity of HD pathology into five grades (0-4).
Interestingly, patients in grade 0, without any apparent
pathology in post mortem observation, have been described
as symptomatic, suggesting that early neuronal dysfunction
induces behavioural changes per se, before neurodegeneration
[50,51]. The initial mild cognitive changes have also been
attributed to basal ganglia pathology, while the severe global
dementia observed in late stage HD are attributed to gross
striatal neuronal atrophy and loss, associated with cortical
neurodegeneration and gliosis. Within the cerebral cortex,
large projection neurons in cortical layers III, V and VI are
the most affected [52-54]. The cortical neurodegeneration has
been associated with the changes in personality and dementia
occurring in late HD .
One of the most striking aspects of HD is the presence of
protein aggregates in the brain. Although previously
reported, relatively little attention was given to this feature
until the presence of intranuclear huntingtin aggregates were
identified in the transgenic R6/2 mice . Immediately
afterwards, N-terminal fragments of mutant huntingtin were
identified in neuronal intranuclear inclusions and dystrophic
neurites in HD cortex and striatum . Aggregates are
present both in striatum
ultrastructurally, both in the cell nucleus, neurites and
neuropil [57-61]. Within the striatum, only 1 to 5% neurons
are stained with N-terminal targeted antibodies [57,61] in
both projecting neurons and interneurons . In adult-onset
HD the predominant form of aggregation is neuritic,
attaining a large percentage of neurons. From the adult-onset
to juvenile cases, aggregation shifts from neuritic to a
predominantly nuclear pattern of aggregation . Neuropil
aggregates were detected in the cerebral cortex of autopsied
pre-symptomatic individuals, suggesting that their presence
in the brain precedes the occurrence of HD neurological
symptoms [57,61]. Despite intensive research on this
subject, the function and relevance of aggregates remain
controversial, and is discussed further in section 3.4.
HD is generally considered to be a slow form of
excitotoxicity. A disproportionate loss of glutamate
receptors, in particular NMDA receptors, is seen in HD post
mortem tissue of symptomatic and pre-symptomatic
patients. This suggests a role for these receptors in the
disease pathogenesis [66-68]. Based on this hypothesis,
different models have been developed. Upon intracranial
injection of quinolinic acid (QA), an agonist of the NMDA
receptors, neuropathological changes reminiscent of HD were
observed in rodents and non-human primates, further
supporting the importance of excitotoxicity in the
pathogenesis of the disease [47,69,70].
In contrast, pre-symptomatic transgenic R6/1 mice
showed a decreased sensitivity to QA-induced striatal
excitotoxicity . Interestingly, the resistance to QA or
malonate (a reversible inhibitor of mitochondrial complex II)
neurotoxicity (described in section 3.2) was shown to be
dependent on the age of the mice and the number of CAG
repeats. It occurred earlier in R6/2 (150 CAG repeats) than in
R6/1 (115 CAG repeats) mice . It has been suggested
that the C-terminal portion of huntingtin, not expressed in
the R6 mice, is required for functional interaction with the
NMDA receptor . Alternatively, early expression of
highly toxic huntingtin fragments during development can
induce unknown developmental modifications that protect
R6 mice from QA toxicity.
The importance of NMDA receptor subunits on HD
pathogenesis has been largely demonstrated by Lynn
Raymond and Michael Hayden. Expression of full-length
mutant huntingtin and NR2B in HEK 293 cells, but not the
NR2A, was accompanied by an increase in apoptosis
[73,74]. This is particularly interesting as the striatum, the
structure most severely affected in HD, was reported to
contain high levels of the NR2B NMDA receptor subunit
, thus justifying the preferential degeneration of striatal
medium spiny neurons in comparison with other regions and
Moreover, the YAC transgenic mice carrying a full-
length huntingtin transgene with 72 CAGs (YAC72) 
were shown to be more prone to NMDA mediated cell death
(via intrastriatal injection of QA) and NMDA receptor-
mediated current amplitude than YAC transgenic mice
expressing full-length huntingtin with 46 CAGs (YAC46) or
wild-type mice . Moreover, measurement of excitatory
postsynaptic currents (EPSCs) in corticostriatal slices from
YAC72 mice and wild-type littermates showed that the ratio
of NMDA receptor- to AMPA receptor-mediated EPSC
amplitude was increased in YAC72 compared to wild-type
mice . Thus, mutant huntingtin may increase NMDA
receptor activity and, consequently, changes in intracellular
calcium, mitochondrial dysfunction, caspases activation and
cell death. These occur through the intrinsic apoptotic
pathway, as reported recently by Zeron et al. (2004) ,
although, curiously, these results were prominent for
YAC46. How mutant huntingtin increases NMDA receptor
activity is still debatable, but could result from a change in
the interaction with cytoskeletal proteins that modulate
receptor function and localization . In fact, expression of
polyglutamine expanded form of huntingtin was shown to
induce tyrosine phosphorylation of NR2B subunits through
the interaction with PSD-95 (a protein mostly associated
and cerebellar cortex,
3. MOLECULAR TARGETS AND THERAPEUTIC
Several lines of evidence suggest that chronic exposure of
neurons to excitatory amino acids, like glutamate may
induce neurodegeneration. Glutamate is released by cortical
efferences in the striatum, where it can activate ionotropic N-
methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-
4-isoxazolepropionate (AMPA) and kainic acid (KA) subtype
of glutamate receptors, as well as metabotropic gultamate
receptors. The inability to respond properly to elevations in
synaptic concentrations of glutamate overexcites neurons,
leading to neuronal death . Activation of the NMDA
receptor allows high levels of calcium entry in neurons.
Calcium triggers different downstream events, such as the
activation of calpains, protein
phospholipases and the consequent production of reactive
oxygen and nitrogen species, which induce cell death by
necrosis and/or apoptosis [64,65]. Thus, the different
NMDA receptor (NMDAR) subtypes have been proposed to
induce different excitotoxic death pathways.
kinase C, DNase,
Molecular Targets and Therapeutic Strategies in Huntington's Disease Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 365
with microtubules that mediates the binding of NMDA
receptor with wild-type huntingtin) and the activation of Src
tyrosine kinase, a PSD-95 associated protein [81,82].
Recently, the type 1 inositol-1,4,5-triphosphate receptor
(IP3R), an intracellular calcium release channel located at the
endoplasmic reticulum, was shown to form a ternary
complex with HAP1A (huntingtin-associated protein 1A)
and huntingtin. In accordance with the mechanism proposed
by the group of Ilya Bezprozvanny, under normal conditions
huntingtin is strongly associated with the NMDA receptor
via PSD-95 and weakly associated with the IP3R. In the
presence of mutant huntingtin there is an increased activity
of NMDA receptor composed of NR2B subunits (most
probably due to a decreased interaction with PSD-95, as
previously reported ) and an increased sensitization of
IP3R (due to the strong binding of mutant huntingtin to the
C-terminal tail of IP3R) by IP3, largely increasing the levels
of cytosolic calcium . This may occur even if low levels
of glutamate are released from the cortical neurons projecting
to the striatum. This rise in intracellular calcium could result
in enhanced neuronal toxicity due to mitochondrial
dysfunction and increased activity of enzymes responsible
for huntingtin proteolysis (see sections 3.2 and 3.3).
Importantly, the protein HAP1, which is expressed in the
medium spiny neurons, is required for changes in
intraneuronal calcium levels and facilitates the activation of
IP3R in the presence of mutant huntingtin, as determined
using HAP1 -/- mice .
In more recent studies, mutant huntingtin was reported to
increase NMDA receptor localization to the synapses by
interacting with huntingtin interacting protein-1 (HIP-1), an
endocytic protein previously shown to regulate clathrin-
mediated endocytosis and to be required for AMPA receptor
internalization . HIP-1 appears to interact directly with
α-actinin and NR2B. Furthermore, primary neurons isolated
from HIP-1-/- mice are protected from NMDA-induced
receptor activation, which was followed by NMDA receptor-
independent delayed apoptosis . The involvement of
apoptotic cell death in 3-NP neurotoxicity has been largely
documented. Chronic administration of 3-NP caused
selective striatal degeneration,
fragmentation, which involved the activation of the c-Jun N-
terminal kinase pathway . Other studies showed 3-NP-
mediated mitochondrial apoptotic features, related with the
translocation of cytochrome c from the mitochondria,
changes in mitochondrial membrane potential, oxidative
stress or an increase in Bax/Bcl-2 in vivo and in vitro (e.g.
[102,103]). The involvement of caspase-1, a class of cysteine
proteases (section 3.3) that are mediators of apoptosis in 3-
NP neurotoxicity was also demonstrated using a caspase-1
dominant-negative mutant mice, which showed smaller 3-
NP striatal lesions .
In the striatum of 3-NP-treated rats, a predominant
activation of calpains over caspase-3 was observed, partially
occurring due to calpain-mediated proteolysis of active
caspase-3 . Although calpain activation could be
confirmed in primary striatal neurons treated with 3-NP, no
significant changes were observed in primary cortical
neurons [106,107]. Moreover,
mitochondrial-dependent apoptotic features mediated by 3-
NP, including cytochrome c release and caspase-3 activation,
were precluded by treatment with FK506, a known inhibitor
of calcineurin or protein phosphatase 2B . FK506 also
decreased mitochondrial Bax and enhanced mitochondrial
Bcl-2 levels , an anti-apoptotic protein shown to
prevent 3-NP mediated cell death . Furthermore,
increased vulnerability of striatal cells derived from mutant
huntingtin knock-in mice to 3-NP appeared to be related to a
non-apoptotic type of cell death involving mitochondrial
According to the 3-NP model, mutant huntingtin would
impair energy metabolism leading to neuronal dysfunction
and death . A considerable amount of data supports
mitochondrial dysfunction in HD brain. Patients experience
weight loss despite high caloric intake, high concentrations
of lactate in striatum and cortex, concomitant with increased
lactate/pyruvate in the cerebrospinal fluid, decreased muscle
phosphocreatine/inorganic phosphate ratio, decreased N-
mitochondrial complexes II/III and IV in basal ganglia [111-
113]. A significant reduction in the activity of mitochondrial
complex IV was observed both in the striatum and cerebral
cortex of brains from 12-week-old R6/2 transgenic mice
. Importantly, significant changes in mitochondrial
membrane potential and reduced mitochondrial calcium
retention capacity were observed in lymphoblasts from HD
patients and in brain mitochondria from the YAC72
transgenic mice . These changes were correlated with
the association of N-terminal huntingtin with the
mitochondria of YAC72 mice, as determined by electron
antibody, which recognizes amino acids 1-256 of huntingtin
and labels aggregated huntingtin . Using isolated
mitochondria from cultured cells, Choo and collaborators
(2004) demonstrated that full-length huntingtin is localized
to the outer mitochondrial membrane . They also
demonstrated that mitochondria incubated in the presence of
mutant huntingtin or isolated from knock-in HD mice had a
analysed by DNA
in cortical neurons,
decreased activity of
using the EM48
3.2. Impaired Energy Metabolism and Mitochondrial
Impaired energy production is another potential
mechanism involved in HD pathogenesis that is in close
relationship with excitotoxicity . Under compromised
energy metabolism normal glutamate concentrations become
toxic in what is generally designated as the “secondary
excitotoxic mechanism”. The selective lesions produced in
the striatum of rodents and non-human primates, following
systemic administration of 3-nitropropionic acid (3-NP),
support this putative mechanism [88-92]; reviewed in [93-
95]. 3-NP irreversibly inhibits succinate dehydrogenase or
mitochondrial complex II, leading to energy deficiency in
vivo with ATP depletion, followed by the activation of
excitatory amino acid receptors and the generation of free
radicals [88,89,96-98]. According to this hypothesis, a loss
of ATP leads to membrane depolarisation and removal of the
voltage-dependent Mg2+ block of the NMDA receptor,
allowing subsequent activation of NMDA receptor, the
influx of calcium and activation of cell death pathways .
In vitro experiments involving primary rat hippocampal
neurons suggested that 3-NP induced cell death through an
initial acute excitotoxic necrosis, resulting from NMDA
366 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4Rego and Pereira de Almeida
reduced calcium threshold for opening of the mitochondrial
permeability transition (MPT) pore and resulting cytochrome
c release, which could be prevented by MPT blockers, such
as cyclosporin A, ATP or EGTA . A decrease in
ATP/ADP ratio in striatal cells derived from knock-in mice
expressing mutant huntingtin further elucidates the relevance
of mitochondrial dysfunction in HD pathogenesis .
Nonetheless, no changes in electron transport chain
activity (complexes I, III and IV), oxidative stress or calcium
homeostasis were detected in HD compared to control cybrid
cell lines, derived from the fusion of HD or control human
platelets and human neuroblastoma SH-SY5Y ρ0 cells
. Since no data on platelet mitochondrial functionality
was reported by these authors, we may envision the
possibility that the platelets from those HD patients had no
deficiencies in mitochondrial function, as previously
described by Gu and collaborators .
In order to counteract the mitochondrial dysfunction and
the bioenergetic defects associated with HD, mitochondrial
neuroprotective agents, namely coenzyme Q10, an essential
molecule for the electron transport chain in the inner
mitochondrial membrane, and creatine, have been tested. As
reported by Koroshetz and collaborators (1997), treatment of
18 HD patients with coenzyme Q10 resulted in a decrease in
lactate concentration in the cortex, which reversed upon
therapy withdrawal . In 2001, the Huntington Study
Group carried out a multicentre controlled trial in 347
patients with early HD, for 30 months, to examine the
effects of coenzyme Q10 and the NMDA antagonist
remacemide. None of these compounds, at the dosages used,
had significant effects in slowing the functional decline
observed in early HD , although untreated HD patients
were recently shown to have lower serum coenzyme Q10
levels than treated HD patients and controls .
Nevertheless, the combination of coenzyme Q10 with
remacemide was effective in increasing the survival of R6/2
transgenic mice by 32% . Supplementation with
creatine, known to increase brain phosphocreatine levels and
stabilize the MPT, was also tested in 41 HD patients, with
stage 1 to 3 . No improvement in functional,
neuromuscular or cognitive status was observed after one
year of creatine intake.
neuroprotective in transgenic HD mouse models, improving
survival and slowing brain atrophy, the development of
motor symptoms and weight loss [123,124].
formation of heterodimers of HIP-1 and a HIP-1 protein
interactor (Hippi) in cells expressing huntingtin with 128
CAG repeats recruited procaspase-8, thus
apoptosis through the extrinsic pathway. However, increased
susceptibility of HD lymphoblasts leading to activation of
initiator caspase-9 and effector caspase-3, but not caspase-8,
was largely associated with mitochondrial depolarisation
. Additionally, NMDA receptor stimulation leading to
activation of caspases -9 and -3 (not caspase-8), was
attenuated by cyclosporin A in cultured striatal neurons
isolated from the YAC46
Polyglutamine-mediated apoptosis occurring through the
intrinsic (mitochondria and caspase-9 mediated) pathway was
recently demonstrated by Ilya Bezprozvanny in striatal
neuronal cultures from YAC128 transgenic mice, following
submitted to prolonged exposure to 100-250 µM glutamate
Proteasome blockade is also strongly implicated in HD
pathogenesis (section 3.5) and previous reports demonstrate
that proteasome dysfunction leads to caspase-dependent
apoptosis [139-142]. Jana and collaborators found a direct
correlation between polyglutamine expansion in huntingtin
or lactacystin blockade of proteasome with a cytoplasmatic
disruption of mitochondrial membrane potential, release of
cytochrome c from the mitochondria, and activation of
caspases -9 and -3 .
fragments have been shown in PC12 cells to increase the
expression of caspase-1 (at the transcriptional level), which
may act as an initiator for the activation of caspase-3, leading
to apoptotis . Similarly, working with R6/2 mice,
Chen and collaborators demonstrated that mutant huntingtin
induces, by an unknown mechanism, caspase-1 upregulation
and activation, followed by inducible nitric oxide synthase
(iNOS) and caspase-3 upregulation and toxicity . The
time-course of caspases activation and changes in pro-
apoptotic proteins of the Bcl-2 family was further elucidated
in the R6/2 mice. In this HD model caspase-1 is the first to
be activated, at 6-9 weeks, followed by the release of
cytochrome c, activation of caspases -9 and -3, increased
tBid and Bax translocation at 9-12 weeks, and further
activation of caspase-8, increased Bim and decreased
phospho-Bad after 12 weeks [144,145]. This caspase cascade
could be blocked by administration of minocycline, a
second-generation tetracycline analogue that is able to cross
the blood-brain barrier . Minocycline was also shown
to inhibit both caspase-independent (occurring through the
apoptosis-inducing factor) and caspase-dependent (occurring
through Smac/Diablo and cytochrome c) mitochondrial
apoptotic pathways in HD models, highlighting the broad
neuroprotective effect of this compound .
Activation of caspase-3, up to certain levels, was
previously suggested to be a normal process that cleaves
substrates without causing apoptosis. Nevertheless, caspases
have been largely implicated in huntingtin cleavage, which
may be responsible for the production of toxic N-terminal
huntingtin fragments. Activated caspases were demonstrated
to cleave both normal and mutant huntingtin near the N-
terminus, further supporting huntingtin as a caspase
substrate [147-150]. Previously, an increased association of
caspase-3 cleaved huntingtin fraction with the membrane
transgenic mice .
However, creatine was
3.3. Caspases Activation and Cell Death
The involvement of apoptosis has been proposed in HD
neurodegeneration by several groups [125-127]. DNA strand
breaks were detected in affected regions of HD patient brains
[128-130]. Moreover, several studies reported that
polyglutamine expansion in huntingtin mediates apoptosis
through caspases activation, in particular caspases 1, 3, 8
and 9 [131-134]. Accordingly, caspase inhibition decreased
polyglutamine-expanded huntingtin toxicity in cells 
and slowed the progression of the pathology and mortality
of transgenic R6/2 mice [134,136].
Caspases activation has been suggested to occur through
oligomerization of caspase 8 in inclusions . The
involvement of caspase-8 was further reported by Gervais
and collaborators . These authors showed that
Molecular Targets and Therapeutic Strategies in Huntington's Disease Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 367
fraction was found, suggesting an involvement in altered
vesicle trafficking in HD . Two caspase-3 cleavage sites
were identified at amino acids 513 and 552 of huntingtin,
whereas one caspase-6 cleavage site was identified at amino
acid 586 . The resulting neurotoxic fragments can
further stimulate proteolysis . Thus, polyglutamine
expanded huntingtin increases
huntingtin aggregation and toxicity [148,149]. There is
evidence of N-terminal fragments of huntingtin in both HD
brains and transgenic mice expressing full-length huntingtin
[57,76]. Working with human post mortem tissue, Kim and
collaborators identified huntingtin fragments in HD brains
with a molecular weight consistent with caspase-3 mediated
cleavage, along with subsequent calpain proteolysis .
Accordingly, activated calpain was detected in the caudate of
human HD tissue and cleavage of huntingtin by calpains was
shown to be polyglutamine-length dependent . The
relevance of calpain activation in HD pathogenesis was
recently demonstrated. Ellerby and collaborators have
mutated two identified calpain cleavage sites in huntingtin
(amino acids 469 and 536) showing decreased susceptibility
to proteolysis, along with decreased aggregation and toxicity
of mutant huntingtin in cell cultures. Interestingly, they
showed that calpain/caspase-derived huntingtin fragments
and activated forms of calpains 7 and 10 are located in the
Overexpression of the anti-apoptotic molecules Bcl-xl
and Bcl-2 was shown to be neuroprotective, further
validating an apoptotic cell death contribution for HD
pathogenesis [132,155]. Transgenic overexpression of Bcl-2,
obtained from crossing R6/2 mice with mice overexpressing
Bcl-2 in neurons, resulted in delayed onset of motor deficits
and an extended survival by 10% in the R6/2 mice .
In addition, other evidence suggests that neuro-
degeneration in HD occurs neither by apoptosis nor by
necrosis, as revealed in the R6 transgenic mice lines and in
post mortem human HD brains . Therefore, it is
possible to assume that, depending on the stage of HD, cell
death by autophagy, in which membrane-bound structures
like the lysosomes engulf intracellular organelles and
participate in the destruction of the cells, also plays a
significant role in HD neurodegeneration. Previously, Kegel
and collaborators reported that association of huntingtin with
the lysosomal enzyme cathepsin D was polyglutamine-
length dependent, suggesting the activation of the
endosomal-lysosomal system and, consequently, of an
autophagic cell death process .
Finally, the success of different anti-apoptotic and
caspase-inhibition strategies in reducing or suppressing
polyglutamine-induced toxicity reinforces its potential as
ubiquitin with intranuclear inclusions suggested that the cell
targets misfolded and aggregated huntingtin, through
ubiquitination, to an ineffective proteasome degradation
(described in section 3.5).
DiFiglia and collaborators confirmed the presence of
accumulation of N-terminal fragments of mutant huntingtin
in intranuclear inclusions and dystrophic neurites in human
brain . Schiling and collaborators also reported neuritic
aggregates in their transgenic model of HD, a feature that
more closely resembles the pattern described for HD tissue
[57,61,158]. This information was confirmed in different
cellular models of HD that documented the presence of
nuclear aggregates of polyglutamine expanded protein and
neurodegeneration [125,126,159,160]. Aggregates were also
identified in all other polyglutamine-expansion diseases
(reviewed in [161-165]). Moreover, transgenic models
expressing truncated fragments of huntingtin [59,158] more
readily and extensively formed inclusions than those
expressing full-length huntingtin [76,166], suggesting a role
of proteolysis in the disease process .
Interestingly, targeting the expression of polyglutamine
expansion huntingtin towards the endoplasmic reticulum or
the mitochondria was recently demonstrated to inhibit its
ability to aggregate, suggesting that unknown cofactors in
the nucleocytosolic compartment enable aggregation of
abnormal proteins .
3.4.1. The mechanism of Aggregation and the Role of
The mechanism of aggregation of huntingtin remains
unclear. Perutz proposed that polyglutamine repeats, when
over 40, destabilize proteins, and induce the formation of
anti-parallel β-strands held together by hydrogen bonds
(polar zippers) . This process of polymerisation is a
molecular property of proteins with more than 40 glutamine
repeats. The resulting structures, designated as hairpins,
would destabilize protein structures, which become
substrates for proteolysis and consequently release N-
terminal fragments of huntingtin. Nuclear translocation,
ubiquitination and aggregation (inside and outside the
nucleus) would follow . Scherzinger and collaborators
demonstrated that huntingtin aggregation was a self-driven
process that occurred in a concentration-dependent and repeat
length-dependent manner in
polyglutamine length threshold was shown to cause
aggregation and pathogenicity
introduction of one additional proline residue in the center of
a Q9 element within the PGQ9 peptide completely blocked
its ability to aggregate .
Green (1993), by analogy to the role of transglutaminases
in mammalian epidermis growth, proposed an alternative
model. Involucrin is a protein of the skin rich in glutamines
that transglutaminases link to the ε-amino groups of lysine
residues (isopeptide bonds) present in other proteins. Green
suggested that polyglutamine cross-linking in the brain by
isopeptide bonds might lead to the formation of multimers
and ultimately to protein
Transglutaminases are present in the brain as a tissue-type I
transglutaminase and a synaptosomal membrane-bound
transglutaminase, and have been found to promote
polymerisation of polyQ expanded huntingtin [171,172].
Several evidences have been found related with the role of
vitro, and the same
3.4. Aggregation and Neuronal Inclusions
One of the distinctive features of HD and polyglutamine
diseases is the formation of neuronal inclusions. Cloning of
the HD gene and production of R6 transgenic mice 
enabled the identification of neuronal intranuclear inclusions
first in mice and later in patient's tissue [57,59]. The
systematic formation of intranuclear inclusions before the
appearance of the phenotype, could indicate a causative role
in HD pathogenesis . Moreover, co-localization of
368 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4Rego and Pereira de Almeida
transglutaminases in the formation of huntingtin aggregates:
i) elevated levels of N(ε)-(γ-L-glutamyl)-L-lysine, a marker
of di-isopeptides, were found in the cerebrospinal fluid
(CSF) of HD patients ; ii) tissue transglutaminase was
increased in HD brain ; iii) colocalization was observed
glutamyl) lysine covalent cross-links and nuclear aggregates
of huntingtin in the frontal cortex of post mortem HD brains
; and iv) administration of the transglutaminase
inhibitor cystamine in a cellular model of DRPLA
(dentatorubral-pallidoluysian atrophy) (Table 1) and in R6/2
transgenic mice has therapeutic
Nevertheless, it has been suggested that the therapeutic
effects of cystamine may be related to its effect on chaperone
overexpression and not to aggregation inhibition .
Apart from inhibiting transgluminases, in more recent
studies, cystamine was demonstrated to inhibit caspase-3
activity and increase the levels of glutathione, prolonging
neuronal survival . A role for cystamine in increasing
the antioxidant activity was further shown through an
increase in the levels of the cellular reducing amino acid L-
cysteine in the R6/2 mice model .
Although the mechanisms involved in the formation of
cortical and striatal perinuclear cytoplasmic aggregates and
intranuclear inclusions of mutant huntingtin are still largely
unclear, the existent data support the hypothesis that
huntingtin is involved in the formation and/or stabilization
of huntingtin protein aggregates in HD and that
transglutaminase 2 cross-links mutant huntingtin through
the regulation of calmodulin [175,181]. Thus, more studies
are needed to evaluate the real potential of directly inhibiting
transglutaminase activity or inhibiting the interaction of
calmodulin with transglutaminase for HD therapy.
3.4.2. Are Huntingtin Aggregates
The role of nuclear inclusions in HD pathogenesis
remains controversial. Some authors considered that it could
be the direct cause of the disease [57,59], while others
believe the huntingtin aggregates are un-related to its
mechanism or that it could even be a detoxification
mechanism of the cell .
Initially, data pointed towards a pathogenic effect of
aggregates. Production of transgenic mice expressing a 146-
unit polyglutamine tract in the mouse hypoxanthine
phosphoribosyltransferase gene (Hprt), a protein not related
with any of the known polyglutamine disease, led to a
phenotype characterized by the formation of nuclear
inclusions and neurological dysfunctions . More
recently, the conditional mouse model of HD showed
huntingtin inclusion body formation and progressive motor
dysfunction when huntingtin expression was turned on.
Administration of doxycycline eliminated huntingtin
expression. The resulting elimination of both the
behavioural phenotype and inclusions reinforced the idea of a
close relationship between
demonstrating that the formation of nuclear inclusions is
reversible . A correlation between the number of
inclusions and polyglutamine number in patients further
suggested a role of inclusions in the pathogenesis of the
Other studies acquitted nuclear inclusions from a direct
responsibility in polyglutamine toxicity. In a HD cellular
model, Saudou and collaborators (1998) blocked huntingtin
ubiquitination, and observed a decrease of huntingtin
aggregation with concomitant increase in toxicity, which led
the authors to conclude that aggregates were part of a cell
detoxifying mechanism . Moreover, in models of
SCA1 (Table 1), reducing aggregation by deletion of a self-
association domain  or preventing ubiquitination, in
mice with a mutation of the E6-AP ubiquitin ligase,
increased toxicity . In other studies it has been possible
to reduce polyglutamine
aggregation, strongly suggesting that aggregates were not the
cause of the disease [186,187]. Kim and collaborators
demonstrated that the formation of inclusions could be
separated from events that control cell death depending on
the caspase inhibitor used . Furthermore, Muchowski
and collaborators showed that disruption of microtubules
avoided aggregation of huntingtin but increased toxicity,
suggesting that free huntingtin is more toxic than nuclear
inclusions . Recently, the group of Huda Y. Zoghbi
working with a knock-in mouse model that recapitulates the
clinical features of spinocerebellar ataxia 7 (SCA7) (Table 1)
found an inverse correlation between neuropathology and the
degree of formation of ataxin-7 nuclear inclusions .
However, Sánchez and collaborators (2003) revealed that
Congo red, known to inhibit oligomerization through the
preferential binding to β-sheets, inhibited polyglutamine-
expansion cell death, by preventing ATP depletion and
caspases -3 and -8 activation, and disrupted preformed
aggregates, as determined by FRET. Furthermore, infusion
of Congo red in symptomatic transgenic R6/2 mice
ameliorated the weight loss, increased motor function and
increased polyglutamine clearance, further revealing the
protective role of anti-amyloid compounds .
Moreover, Tanaka and collaborators, assuming that the
aggregates are toxic, selected various disaccharides based on
their ability to inhibit polyglutamine-mediated protein
aggregation. The most active, trehalose, was orally
administered to a transgenic mouse model of Huntington’s
disease (R6/2 mice) and has been shown to decrease
polyglutamine aggregates in cerebrum and liver, improve
motor dysfunction and extend lifespan. This approach
appears to be promising since no toxicity arising from oral
trehalose administration was reported .
toxicity without affecting
cross-linking of mutant
the Cause of
these two variables,
3.5. Proteasome Impairment
The ubiquitin-proteasome pathway (UPP) is involved in
cellular quality control
unassembled, or damaged proteins that could otherwise form
potentially toxic aggregates
neurodegenerative diseases there is an accumulation of
ubiquitinated protein aggregates suggesting a link between
UPP and neurodegeneration . Interestingly, wild-type
ataxin-3, a poly-ubiquitin binding protein reported to have a
deubiquitinating activity, is sequestered together with
ubiquitin in protein aggregates of several polyglutamine
expansion diseases [195-197]. A reduction of proteasome
activity with aging could explain the late-onset of
polyglutamine diseases .
by degrading misfolded,
[192,193]. In most
Molecular Targets and Therapeutic Strategies in Huntington's Disease Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 369
Different findings support that aggregation of huntingtin,
followed by ubiquitination leads to proteasome impairment.
In polyglutamine disorders, proteasome components have
been associated with intranuclear inclusions [57,59,143,199-
202]. Moreover, drug-induced experimental proteasome
blockade increases protein aggregation [143,203-205]. The
work by Kopito’s group suggested that the presence of
polyglutamine expanded huntingtin fragments inhibits
proteasome function . In fact, polyglutamine proteins
appear to be trapped within the proteasome .
Furthermore, blocking huntingtin expression in Yamamoto’s
conditional model of HD, either in vivo or in vitro, lead to
rapid proteasome mediated clearance of both wild type and
mutant huntingtin, disappearance of inclusions and later on,
the complete remission of the phenotype [182,198].
The theory of proteasome impairment suggests that the
blockade of proteasome by misfolded polyglutamine
expanded proteins may induce the accumulation of other
proteins and transcription factors, further impairing the
proteasome function and promoting protein accumulation
and aggregation by a positive-feedback mechanism.
Moreover, sequestration of anti-apoptotic factors and
transcription factors may contribute to cell death.
Nevertheless, a recent work using a mouse model that
expresses a green fluorescent protein (GFP)-based reporter
substrate (Ub(G76V)-GFP) of the UPP and ataxin-7 found
no evidence for general UPP impairment, or reduction of
proteasome activity . In spite of these observations,
proteasome activity seems to counteract accumulation of
both soluble and aggregated huntingtin , and therefore a
logical therapeutic approach would be to boost its
In contrast to ubiquitination, SUMOylation (a post-
translational modification resulting from the covalent
attachment of small ubiquitin-like modifiers (SUMO) to
lysine residues) of mutant huntingtin was recently proposed
to interfere with HD pathogenesis by decreasing its ability to
form aggregates . SUMOylation can also promote
transcription repression and exacerbate neurodegeneration, as
demonstrated by mutation of lysine residues within the first
17 amino acids of huntingtin . The SUMO pathway
parallels the classical ubiquitination pathway, through
activation involving enzyme E1, conjugation involving
enzyme E2 and substrate modification through the
cooperative association of E2 and E3 ligases. Thus,
interfering with protein SUMOylation could bring about a
new therapeutic candidate against neurodegenerative diseases.
Alternatively, chaperones may modify the mutant
proteins solubility and promote their degradation .
chaperones, because they assist protein folding, oligomeric
assembly, transport to a particular subcellular compartment,
controlled switching between active/inactive conformations,
and recovery of native configuration after unfolding
Mutated proteins, particularly with polyglutamine
expansions, tend to unfold, aggregate, and deposit. Several
lines of evidence support a role for chaperones in preventing
polyglutamine toxicity: i) chaperones co-localize with
aggregates in polyglutamine
[202,205,215]; ii) overexpression of chaperones has been
demonstrated to decrease polyglutamine toxicity in different
models of disease [186,199,216-219].
Endogenous polyglutamine length-dependent induction
of Hsp70 was shown in a HD mammalian cellular model
expressing truncated N-terminal huntingtin. Overexpression
of a Hsp40 member (Hdj-1), alone or in combination with
Hsp70 (Hsc70) significantly reduced huntingtin aggregation
and toxicity . Muchowski and collaborators, working
both in a cell-free system and with yeast, also observed that
overexpression of chaperones (Hsp40 and Hsp70) suppress or
reduce aggregation .
In contrast, suppression of toxicity without a decrease in
protein aggregation was shown in a HD fly model ,
similarly to what had been previously described in an SCA-
1 model . The authors isolated two genes coding for
molecules containing chaperone-related J domains, one of
them homologous to human Hsp40/Hdj-1 and able to
Therefore, chaperone detoxification
accompanied by a decrease in protein aggregation. A decrease
in polyglutamine-induced cell death, with no changes in
protein aggregation, was further associated with a
suppression of formation of reactive oxygen species upon
expression of Hsp27, in neuronal and non-neuronal cells
. Chaperone neuroprotection, mediated by Hsp 40, Hsp
70, and N-ethylmaleimide-sensitive factor, was also reported
to involve an inhibition of caspases -3 and 9 activation by
huntingtin, independently of the inhibition of aggregation,
which was achieved only with Hsp 40 . Recently,
Schaffar and collaborators (2004) further supported the
beneficial effects of Hsp70/Hsp40 by demonstrating that
these chaperones inhibit
interaction of huntingtin with the transcription factor TATA
box-binding protein or TBP (see section 3.7) .
Unexpectedly, chaperones can also promote inclusion
formation . Accordingly, in a yeast model of
huntingtin, deletion of Hsp104 expression completely
eliminated huntingtin aggregation, suggesting that this
chaperone can have a propagation role in polyglutamine
expanded aggregation . Thus, the existence of
polyglutamine tracts in a soluble form is prolonged in
hsp104 yeast mutants. Nevertheless, the requirement of
Hsp104 function for aggregate formation of short
polyglutamine tracts was shown to be bypassed if long
polyglutamine tracts were present .
Besides heat shock proteins, other small molecules have
been reported to have a chaperone-like activity such as the
osmolytes that unicellular organisms synthesize upon
temperature or ionic strength stress. The previously
models and patients
Stress, like heat, ethanol, heavy metals, amino acid
analogs and anoxia, cause denaturation of proteins, which
tend to aggregate and precipitate. In response to these
stresses, cells synthesize a set of proteins, collectively
referred as heat shock protein(s) (Hsp)  and
denominated according to their molecular weight . The
Hsp are proteins containing a functional element in their
promoter that upon heat stimuli induce transcription
[211,212]. Most of these proteins are designated as
370 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4Rego and Pereira de Almeida
described success of trehalose administration to R6/2 mice
may be attributed to a chaperone like-activity, which
presumably allowed stabilization of the partially unfolded
polyglutamine-containing protein .
Chaperones have multiple roles and its mechanisms of
detoxification are complex and remain largely unknown. It
has been suggested that chaperone could protect against
formation of amyloid-like aggregates, which instead, in the
presence of chaperones, give rise to amorphous aggregates
amenable to proteasome
chaperones could prevent aggregated protein from recruiting
and inactivating other glutamine-rich proteins . In more
recent data, the group of Paul Muchowski reported that
Hsp70 and Hsp40 can modulate polyglutamine aggregates
by decreasing the formation of spherical and annular
oligomeric structures induced by mutant huntingtin, as
demonstrated by atomic force microscopy .
In conclusion, chaperones interact with polyglutamine-
expanded fragments in the direct proportion of their
polyglutamine length. They co-localize in model systems
with aggregates and can suppress cell toxicity accompanied
or not by simultaneous decrease of aggregation. Because in
their normal stress response chaperones promote both
solubilization of misfolded proteins and inhibit caspase
activation, it remains unclear which is their dominant
neuroprotective mechanism. They are, however, a promising
therapeutic approach, which should be evaluated in
mammalian models of HD.
DRPLA (caused by polyglutamine expansions in atrophin-1
- Table 1) patients [233,240] as well as in SBMA (caused by
androgen receptor polyglutamine expansion – Table 1)
models and human tissue . Acetyltransferases promote
transcription by acetylating histones, an effect that is in
dynamic equilibrium with histone deacetylators, which have
the opposite effect. Decreasing acetyltransferases activity
results in reduced transcription of the genes under its
control. Different studies identified decreased acetylation and
polyglutamine expansions in yeast and mammalian cell
culture [233,241]. Furthermore, it has recently been shown
that conditional disruption of CREB function in brain leads
to neurodegeneration and a striatal phenotype reminiscent of
HD further supporting CREB’s role in HD pathogenesis
. Unexpectedly, Obrietan and Hoyt (2004) found a
significant increase in CRE-dependent transcription in the
striatum, hippocampus and cortex, by cross breeding R6/2
HD transgenic mice with CRE-β-galactosidase reporter gene
transgenic mice, resulting a HD transgenic mouse with
pathological changes similar to the R6/2 .
Reasoning that up-regulating CBP would counteract the
effects due to its sequestration, Nucifora and collaborators
 and McCampbel and collaborators  reversed
toxicity induced by polyglutamine expanded huntingtin or
atrophin-1 by CBP overexpression, and further demonstrated
the importance of this pathogenic mechanism. In addition,
expression of Sp1 and the transcription coactivator
TAFII130 (a human TBP-associated factor or TAF, known
to interact with various cell activators, such as Sp1 and
CREB) reversed the transcription deregulation of dopamine
D2 receptor gene and protected from cell toxicity in striatal
cell cultures expressing mutant huntingtin with 75
Using another strategy, Steffan and collaborators 
compensated for the loss of acetyltransferase activity by
using inhibitors of histone deacetylases (iHDACs). Histone
deacetylases are classified into classes I (HDACs 1, 2, 3 and
8) and II (HDACs 4, 5, 6, 7 and 9), which have similar
catalytic domains, and class III, composed of sirtuins (Sir),
which are similar to the NAD+-dependent yeast SIR2
proteins and are structurally and catalytically different from
classes I and II. Administering iHDACs reversed the
decrease in acetylated H3 and H4, arrested neurodegeneration
and reduced lethality induced by polyglutamines in vitro in
cell lines and in vivo in Drosophila models [244,245].
Although many studies have reported the use of iHDACs as
anticancer agents, these compounds have been tested in
several models of HD to increase the levels of histone
acetylation and gene expression. The iHDAC suberoylanilide
hydroxamic acid (SAHA), which crosses the blood-brain
barrier and could be administered orally in drinking water,
increased histone (H2A, H2B, H3 and H4) acetylation and
significantly improved the motor deficits of transgenic R6/2
mice . Two other iHDAC, sodium butyrate and
phenylbutyrate, administered by intraperitoneal injection to
the R6/2  and the N171-82Q transgenic mice models
, respectively, were also shown to prevent the decrease
in striatal neuronal atrophy, increase protein acetylation, alter
gene expression, and increase survival. Administration of
phenylbutyrate to HD mice further attenuated increased
histone methylation, induced the expression of glutathione-
in the presence of
3.7. Transcriptional Dysfunction
Polyglutamine recruitment of transcription factors may
disrupt gene transcription [202,225] and have a determinant
role in HD pathogenesis (reviewed in [226,227]). Different
studies showed that N-terminal huntingtin fragments interact
with, and recruit other proteins and that nuclear localization
of mutant huntingtin contributes to its pathogenicity
[155,228]. During the process of protein aggregation in the
nucleus, mutant huntingtin appears to interact particularly
with proteins containing polyglutamine domains, as it is the
case of several transcription factors, such as the cAMP-
responsive element-binding protein (CREB)-binding protein
(CBP), TATA box binding protein (TBP), and specificity
protein 1 (Sp1) [229-233].
TBP has been described to co-localize with huntingtin
aggregates in HD post mortem brains  and an expansion
of polyglutamine repeats within the TBP gene is responsible
for a new polyglutamine disease, SCA17 (Table 1) .
Furthermore, nuclear accumulation of monomers or soluble
oligomers of mutant huntingtin, implicated in cell toxicity,
were shown to interact with the benign polyglutamine tract
of TBP, destabilizing its function . A soluble form of
mutant huntingtin also interacts with the transcriptional
activator Sp1 thus reducing the expression of the
corresponding Sp1-regulated genes [236,237].
An important mechanism leading to transcription
blockade may involve acetyltransferases inhibition of
activity. CBP is an acetyltransferase enzyme with an 18
glutamine domain [227,238] that has been shown to co-
aggregate with huntingtin in vitro , in the R6/2 HD
transgenic model and in post mortem brains of HD and
Molecular Targets and Therapeutic Strategies in Huntington's Disease Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 371
S-transferase and a proteasome subunit, and repressed the
expression of caspases -8 and -9, overall having a
neuroprotective role . iHDACs were also reported to
prevent oxidative stress-mediated neuronal death by
enhancing Sp1 acetylation and Sp1-dependent gene
expression , suggesting that these compounds may be
used in other neuropathological situations associated with
increased production of reactive oxygen species.
The transcriptional dysfunction hypothesis is also
supported by observations of selective decreased mRNA
levels, particularly of enkephalin and substance P messenger
RNA in the striatum of early grade HD  and of
dopamine D1 and D2 receptor gene expression in the
striatum of HD patients . These observations were
confirmed in transgenic R6/2 mice [252,253], where
decreased adenosine A2A receptors mRNA levels were also
observed . Evidence of decreased gene transcription in
HD mice comes also from gene expression arrays on DNA
microchips . Moreover, in studies using human
fibroblasts from HD patients, it has been shown that N-
terminal fragments of huntingtin repress transcription .
Wyttenbach and collaborators
doxycycline inducible PC12 cells that express huntingtin
exon-1 with increasing polyglutamine tract, also observed an
early decrease in VGF8a gene expression possibly because it
is CRE-regulated. VGF has an important role in energy
homeostasis and therefore this observation is consistent with
the depression in regulation of energy balance observed in
HD patients. Under this perspective, Calkins and
collaborators  have recently described that the nuclear
factor erythroid 2-related
transcription, known to translocate to the nucleus and bind
to the antioxidant response element (ARE), regulating the
transcription of cytoprotective genes, is important for
protecting against inhibition of mitochondrial complex II-
mediated toxicity in vitro (using primary cortical cultures)
and in vivo .
Importantly, Zuccato and collaborators  described the
decrease in cortical transcription of BDNF in the presence of
mutant huntingtin, thus reducing trophic support to the
striatum . This change in BDNF gene transcription was
associated with the abnormal accumulation of the repressor
element-1 transcription factor/neuron restrictive silencer
factor (REST/NRSF) in the nucleus, due to impairment of
its retention by mutant huntingtin in the cytoplasm, in
contrast to the ability of wild-type huntingtin . As a
consequence, in the presence of polyglutamine-expanded
huntingtin, the transcription factor REST/NRSF binds to
the neuron restrictive silencer element (NRSE), amplifying
its activity and thus silencing BDNF expression .
Moreover, a microarray analysis of inducible striatal cells
expressing the first 548 amino acids of wild-type or mutant
huntingtin in a regulated
tetracycline/doxycycline-responsive element, were shown to
differentially express genes involved in cell signalling,
transcription, lipid metabolism (cholesterol and fatty acid)
and vesicle trafficking , suggesting that changes in gene
expression trigger polyglutamine cell toxicity. Premature
decreased expression of genes
transduction and calcium homeostasis were also reported in
transgenic mice models of SCA1, expressing polyglutamine-
expanded ataxin-1 (Table 1), before the onset of symptoms,
or in SCA1 human tissue .
In conclusion, transcription repression could be an
important mechanism in the pathogenesis of HD.
Accordingly, the regional selectivity of the pathology can
result from the genes whose transcription is impaired or
modified [253,259,260]. Nevertheless, it is important to
note that the transcription deregulation hypothesis does not
exclude other mechanisms of pathogenesis, as modifications
of gene transcription of specific genes can potentiate other
mechanisms of cell death, like excitotoxicity and apoptosis.
, working with
3.8. Trophic Factor Starvation and Deregulation of
Neurotrophic factors are growth factors known to regulate
survival and differentiation of neurons (reviewed in
[261,262]). It has been suggested that neurotrophic factors
could slow, arrest or even promote regeneration in several
Since clinical genetic analysis allows the detection of
people at risk of becoming HD patients prior to the
development of symptoms, therefore, a neuroprotective
approach with trophic factors, aiming at reducing or
preventing the neuronal death occurring in HD, could be
initiated before striatal neurodegeneration. Different
neurotrophic factors, namely nerve growth factor (NGF),
BDNF, glial cell line-derived neurotrophic factor (GDNF) or
ciliary neurotrophic factor (CNTF), have shown potent
protective effects in animal models of HD [155,263-268]; for
review see .
NGF has been shown to protect cholinergic striatal
neurons in the QA and 3-NP models of HD , and to
preserve TrkA and choline acetyltransferase mRNA
expression levels [271,272].
administration protects solely cholinergic neurons, the only
striatal neurons expressing TrkA receptors, and therefore, the
main striatal population attained in HD, the GABAergic
neurons, are not protected by NGF delivery [270,273].
BDNF is another neurotrophin that has been suggested to
have therapeutic value in HD. BDNF is anterogradely
transported from the cortex to the striatum and its expression
is increased upon striatal lesioning , suggesting that the
corticostriatal circuitry is essential for survival of striatal
neurons under normal and pathological conditions. Thus,
under normal conditions, TrkB mRNA is present in the
striatum, but BDNF mRNA is not . Moreover, BDNF
expression is upregulated by wild-type huntingtin, therefore
suggesting that it provides trophic support for both striatal
and cortical neurons. Importantly, this beneficial effect is
lost with mutated huntingtin , and a selective BDNF
loss of expression was observed in CNS areas degenerating
in HD patients . Moreover, wild-type huntingtin,
previously shown to have an anti-apoptotic effect by
inhibiting the cleavage of procaspase-9 [277,278], promotes
the vesicular transport of BDNF along the microtubules
through huntingtin-associated protein-1 (HAP-1) and the
p150Glued subunit of dynactin . In contrast, vesicular
BDNF transport is impaired by mutant huntingtin ,
implying a decreased release of BDNF from the cortical
projections and, consequently, a deleterious effect on striatal
manner, driven by a
involved in signal
372 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4Rego and Pereira de Almeida
neurons. Interestingly, production of conditional BDNF
mutant mice that lack cortical BDNF, by the Cre-loxP
recombination system, recapitulated most symptoms of HD
mice models . Furthermore, this study showed that the
absence of anterograde cortical BDNF leads to early striatal
deficits and age-dependent neuronal loss .
Previous studies have clearly pointed out that the early
degeneration of the corticostriatal pathway may be due to the
accumulation of mutant huntingtin and the consequent
dysfunction of the axonal transport [281,282]. While wild-
type huntingtin appears to be required for normal axonal
transport, expression of mutant human huntingtin exon-1 in
larval neurons of Drosophila caused the disruption of axonal
transport and neuronal cell death . In fact, cytoskeleton
destabilization appears to precede the nuclear accumulation
of mutant huntingtin, and taxol, a compound known to
stabilize the microtubules, further demonstrated this by
preventing polyglutamine-induced cell death . Under
this perspective, doxycycline-inducible expression of mutant
huntingtin was shown to block calcium-induced exocytosis
in non-differentiated PC12 cells, concomitantly with a
depletion in complexin II, a protein that appears to control
the SNARE complex .
Delivery of BDNF to the CNS, using either adenoviral
or adeno-associated viral vectors-gene delivery, has shown
neuroprotective effects in the QA rat model of HD
[286,287]. These data suggest that neurotrophins and
particularly BDNF may have a role in HD pathogenesis and
could be used in HD therapy.
GDNF is a potent survival factor for dopaminergic
neurons and also promotes survival of noradrenergic,
cholinergic, sympathetic, parasympathetic and sensory
neurons . GDNF transmits its signal by interaction
with a multicomponent receptor complex containing the
receptor tyrosine kinase
phosphatidylinositol (GPI)-linked receptor, GDNF family
receptor alpha1 (GFR-alpha 1) .
Although most studies with GDNF have been focused on
the study of neuroprotective effects on dopaminergic neurons
[290,291], with a particular emphasis on the neuroprotection
of Parkinson’s disease, it has been shown that GDNF also
protects noradrenergic neurons, calbindin-immunoreactive
and striatonigral neurons in various experimental paradigms.
In the striatum, both RET and GFR-alpha 1 are expressed
and GDNF has been shown to have neuroprotective effects in
QA lesioned rats [292-294]. GDNF increased tyrosine
hydroxylase staining in both intact and lesioned striata and
protected a fraction of calbindin-positive, but not
parvalbumin immunoreactive striatal neurons against QA
lesion . In addition, GDNF preserved neuronal
expression of glutamic acid decarboxylase, preprotachynin A
and prodynorphin . Protective effects were also
obtained when either recombinant GDNF  or an AAV
vector encoding GDNF were administered in a chronic 3-NP
model of HD in rats . Finally, a neuroprotective effect
was also reported with neurturin, a GDNF analog. The effect
on striatal projection neurons was reported to be more
specific and efficient with neurturin than with GDNF .
Moreover, work with cultured mouse astrocytes suggests
that riluzole upregulates the expression of different
neurotrophic factors, namely GDNF, contributing to the
neuroprotective effect of this anti-excitotoxic agent .
CNTF belongs to the family of neurokins, a group of
cytokines with multiple actions in the CNS and other
tissues (reviewed in ). CNTF was first identified in
avian ocular tissue and named for its ability to support
survival of parasympathetic neurons from chick ciliary
ganglion [300,301]. It was later shown to support survival
and differentiation of central and peripheral neurons,
including sympathetic, embryonic motor, striatal, thalamic
and hippocampal neurons [302-305]. CNTF is considered an
injury protein that upon damage to the brain is released from
astrocytes, the brain sources of CNTF .
CNTF interacts with a tripartite complex receptor at the
cell surface composed of CNTFRalpha and two beta
subunits, gp130 and LIFR, which following formation of
the CNTF/CNTFRalpha/gp130/LIFR complex activate a
phosphorylation cascade involving the phosphorylation of
transcription factors (STATs), which dimerize and
translocate to the nucleus, resulting in the transcription of
target genes, particularly anti-apoptotic genes of the Bcl
family [307,308]. CNTF has also been implicated in
activation of other cell survival pathways, particularly the
phosphatidylinositol 3-kinase and the mitogen-activated
protein kinase pathways . In addition to its direct
effects over cells, CNTF can also have indirect effects.
CNTF is upregulated in astrocytes in response to injury and
hypertrophy and modification of phenotype [310-315].
Moreover, CNTF astrocyte activation induces the production
of other trophic factors, particularly fibroblast growth factor
(FGF-2) and NGF, and enhances astrocyte detoxification
capacity, thus supporting neuronal survival . The
CNTFRalpha can also be released from the cell membrane,
by phospholipase C-mediated cleavage. The resulting
soluble form can promote binding to the gp130/LIFR dimer
in cells that are not highly responsive to CNTF alone
[317,318]. Furthermore, as it happens with
neurotrophic factors, CNTF is internalised at distal axons
and retrogradely transported to cell bodies. This allows
CNTF to produce effects in regions distant from the
administration area .
Anderson and collaborators performed a systematic study
of the therapeutic properties of various neurotrophic factors,
using the QA model. BDNF, NGF and neurotrophin 3 (NT-
3) did not elicit any protection of striatal output neurons
against QA, while CNTF afforded marked neuroprotection
. Several studies confirmed the neuroprotective effect of
CNTF at neurochemical, neuropathological and behavioural
levels in different toxin based animal models of HD .
CNTF administration was also shown to produce
neuroprotective effects in a genetic in vitro model of HD
Previously described side-effects of systemic delivered
CNTF, dry cough, weight loss and acute phase response,
have driven research into alternative delivery systems,
particularly into the use of macroencapsulated cells
engineered to produce CNTF. This approach has been used
by the group of Patrick Aebischer in a clinical trial for
amyotrophic lateral sclerosis that proved the safety and
feasibility of the approach . The delivery of CNTF by
CNTF induces astrocyte
RET and a glycosyl-
Molecular Targets and Therapeutic Strategies in Huntington's Disease Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 373
encapsulated genetically modified cells in HD has later been
addressed. Encouraging results were obtained with BHK
cells secreting the human CNTF, when implanted in the
striata of rodent and non-human primate, in acute and semi-
chronic toxic models of HD [265,321-323]. The preclinical
studies led to a clinical trial using this approach which
ended recently [324,325]. The study aimed at evaluating the
safety of intracerebral administration of CNTF in subjects
with HD, using a device formed by a semipermeable
membrane encapsulating up to 106 human CNTF-producing
BHK cells, releasing 0.15-0.5 µg CNTF/day. Six subjects
with stage 1 or 2 HD had one capsule implanted into the
right lateral ventricle; the capsule was retrieved and
exchanged for a new one every 6 months, over a total period
of 2 years. Improvements in electrophysiological results and
no toxicity were observed, in correlation with capsules
releasing the largest amount of CNTF, although CNTF
release was low in 13 of 24 cases. The study showed the
safety, feasibility, and tolerability of the procedure, but also
showed that technical improvements are still needed to
overcome the heterogeneous cell survival and the resulting
decrease in CNTF release. Furthermore, it remains to be
elucidated if this is the best delivery system to ensure a very
An alternative approach consists in making the cells
express CNTF locally, by transducing the targeted brain
region with viral vectors encoding CNTF. Accordingly,
transduction of the rat brain with lentiviral vectors encoding
CNTF led to behavioural,
immunohistochemical neuroprotection in the QA model of
HD . The approach has been refined to allow regulation
of gene expression by engineering tetracycline-regulated
lentiviral vectors encoding human CNTF. A dose-dependent
neuroprotective effect was observed in this model of HD
. The effects of long term lentiviral-mediated
expression of CNTF in the striatum of HD transgenic mice
(YAC72 mice) were also evaluated . CNTF expression
reduced the over activity observed in YAC72 mice and the
number of striatal dark cells . The viral vector approach
has considerable interest in a preclinical setting for research
purposes. Nevertheless, there are safety concerns, which until
now have precluded the clinical use of lentiviral vectors.
Other pro-survival effects may be related with the
activation of the Akt signalling by the insulin-like growth
factor 1 (IGF-1), which is involved in phosphorylation of
huntingtin on serine 421, thus abrogating polyglutamine
toxicity . Nevertheless, phosphatidylinositol 3-kinase-
dependent Akt activation in mutant striatal cells (derived
from the knock-in mice) was associated with an early pro-
survival response apparently associated with NMDA receptor
activation and thus Ca2+-dependent .
The putative mechanisms of HD pathogenesis are
represented in Figure 2.
the early strategies, the ideal therapy, but highly
challenging, would involve gene repair . Alternatively,
gene-silencing techniques, aiming at reducing intracellular
concentration of huntingtin or other polyglutamine carrying
proteins, are a promising strategy for therapy of
polyglutamine diseases. Downregulation of mRNA can be
done through anti-sense technology [331,332] or RNA
interference. A different, downstream intervention consists in
promoting huntingtin removal through intrabodies.
The anti-sense (AS) approach allows downregulation of
gene expression by blocking translation of mRNA, mainly
through the action of RNase H ribonuclease. Boado and
collaborators generated a series of AS oligodeoxynucleotides
(ODNs) complementary to the huntingtin transcript, which
markedly decreased the abundance of the huntingtin-green
fluorescence fusion protein to 40-46% of the control levels
. Gene silencing by double-stranded RNAs (dsRNAs)
designated as RNA interference induces the sustained down-
regulation of the target gene by promoting mRNA
degradation. This technology has recently been tested in
mammalian and Drosophila cells carrying a polyglutamine
expanded SBMA transgene . Different dsRNAs were
able to inhibit expression of non-repetitive sequence
transcripts of the truncated human androgen receptor and to
rescue mammalian cells from polyglutamine toxicity. The
dilemma of silencing techniques is that it is not known if
the cells can withstand a depletion of huntingtin that could
compromise its normal role in the cell. A silencing modality
that would allow a selective blockade of mutant huntingtin
expression would be highly desirable. Such selective
silencing has been achieved by the group of Henry Paulson
with dsRNAs in cell models of Machado-Joseph
disease/SCA3 (Table 1). The authors targeted a single-
nucleotide polymorphism linked to the mutant SCA3 allele
with small interfering RNAs and observed exclusive
silencing of mutant ataxin-3 allele while sparing expression
of the WT allele .
More recently, Davidson and collaborators showed that
RNAi gene therapy for ataxin-1 can improve cellular and
behavioural characteristics in a SCA1 mouse model. In the
case of SCA1 the silencing of both wild-type and mutant
ataxin-1 would probably not be so problematic as in other
polyglutamine expansion diseases because ataxin-1 knockout
mice do not display major pathologic features . These
studies suggest that RNAi is a highly promising technology
for therapy of dominant neurodegenerative diseases.
Another approach involves
toxicity and clearance through specific binding to other
proteins. Intrabodies are a modality of intracellular
immunization that allows suppression of specific proteins
. Intrabodies are engineered single-chain antibodies in
which the variable domain of the heavy chain is joined to
the variable domain of the light chain through a peptide
linker, preserving the specificity and affinity of the parent
antibody, and designated as single-chain variable region
fragment antibodies (scFv). In an in vitro model of HD,
Lecerf and collaborators (2001) showed that a human scFv
antibody specific to the N-terminal 17 residues of huntingtin
protein was able to counteract aggregate formation. The
authors claim that the intrabody binds to huntingtin,
decreases huntingtin propensity to form aggregates, and
4. GENE AND PROTEIN SILENCING AND CELL
REPLACEMENT THERAPY IN HD
Most of previously described strategies, as they envision
therapy after huntingtin protein synthesis, can be considered
late approaches. In opposition, early interventions aim at
blocking the mutant protein production in the cell. Among
374 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4Rego and Pereira de Almeida
Fig. (2). Potential mechanisms inducing HD pathogenesis include excitotoxicity, mitochondrial dysfunction, apoptosis, proteasome
blockade and transcription impairment, either alone or combined with each other. The polyglutamine expanded huntingtin gene is
transcribed and translated into a mutant huntingtin protein, which is cleaved by caspases into huntingtin fragments. Overactivation
of caspases by mutant huntingtin can lead to apoptosis. Mutant huntingtin or its fragments can interact with the NMDA receptor
promoting glutamate-mediated excitotoxicity. Mutant huntingtin or its fragments may also associate with mitochondria leading to
mitochondrial dysfunction. The huntingtin fragments are ubiquitinated and aggregate in the cytoplasm and nucleus.
Polyubiquitination targets the fragments to the proteasome, which is consequently blocked leading to cellular toxicity. In the
nucleus, huntingtin fragments bind different molecules, particularly transcription factors that have polyglutamine tracts leading to
forms a soluble complex that undergoes normal protein
turnover . Then, Ali Khoshnan generated scFvs
antibodies that recognize the huntingtin polyproline domain
and significantly inhibited huntingtin aggregation and cell
death, demonstrating its potential therapeutic value in HD
. Analogous strategies with either a targeted peptide
 or a monoclonal antibody , targeting elongated
polyglutamine, showed efficacy on in vitro models. In vivo
studies will be important to confirm the therapeutic potential
of these protein-silencing strategies. Nevertheless, and as it
happens with the previous described gene silencing
approaches, binding huntingtin with intrabodies could block
the normal huntingtin function. A promising alternative
would involve the use of intrabodies that selectively
recognize mutant huntingtin.
An alternative approach consists in HD restorative
therapy through the transplantation of neural cells from
several sources that replace the dying striatal neurons.
Transplantation of human fetal striatal tissue into the
striatum of one patient with clinical features of HD showed
the survival of the fetal neural cells and the reconstitution of
damaged neuronal connections, which were not affected by
the genetically predetermined disease process. Unfortunately,
the patient died 18 months after transplantation from
cardiovascular disease . Grafting of human fetal striatal
neuroblasts into the striatum was further performed in five
patients with mild to moderate HD. Three out of five
patients showed increased metabolic activity, concomitantly
with an improvement of motor and cognitive functions.
Nevertheless, two other HD patients showed progressive
decline upon transplantation
improvement of the three HD patients was further associated
with an increase in cortical metabolism, as analysed in a
follow up studied by positron emission tomography
measurements of brain glucose metabolism . The
feasibility and survival of grafts were further demonstrated in
other studies after unilateral or bilateral transplantation of
human fetal striatal tissue in symptomatic HD patients
[343,344]. Although fetal neural transplant therapies have
become clinically important, the establishment of their
efficacy and their real benefits requires the analysis of a
larger number of patients, and, in particular, a deep
investigation into the basic mechanisms of neural survival.
Nevertheless, the low availability of fetal cells and ethical
concerns prevent progress in this area. Therefore the use of
neural stem cells has been proposed as an alternative source
. The clinical
Molecular Targets and Therapeutic Strategies in Huntington's Disease Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 375
of material for transplantation. In recent studies, intrastriatal
rat transplantation with human neural stem cells one week
after QA injection  or one week before 3-NP systemic
administration  was shown to restore motor deficits and
delay neurodegeneration. Nevertheless, implantation of
human-derived immortalized cell line in rats submitted to an
excitotoxic lesion did not cause significant beneficial effects
. Additionally, predifferentiation of a neural stem cell
line into a homogenous population of cells with a
GABAergic phenotype and their further transplantation into
the rat striatum subjected to QA injection showed a stable
maintenance of the acquired phenotype and further neurite
processing , supporting cell replacement strategies for
While neural (stem) cell transplantation still requires
more intensive research, a complementary therapy could be
based on boosting adult brain neurogenesis. Recent reports
have looked at neurogenesis in human and animal models of
HD. In the adult postmortem human brain, a significant
increase in cell proliferation was observed in the
subependymal layer in HD, compared with control brains
. An increase in cell proliferation in human HD brains
increased with pathological severity and CAG repeats .
Concordantly, an increased
neurogenesis was observed in the subventricular zone of
adult rats lesioned with QA, highly suggestive of formation
of new neurons and their migration to damaged areas of the
striatum . Nonetheless, decreased neurogenesis has been
observed in the hippocampus (dentate gyrus) of older (20-
week-old) R6/1  or 12-week-old R6/2  transgenic
= Brain-derived neurotrophic factor
= CREB-binding protein
= Ciliary neurotrophic factor
= cAMP-responsive element-binding protein
= Fibroblast growth factor 2 or basic fibroblast
= Glial cell line-derived neurotrophic factor
= GDNF family receptor
= Huntingtin-associated protein 1
= Huntington’s disease
= Huntingtin interacting protein-1
= Insulin-like growth factor 1
iHDACs = Inhibitors of histone deacetylases
IP3R = Inositol-1,4,5-triphosphate receptor
KA= Kainic acid
MPT = Mitochondrial permeability transition
NGF = Nerve growth factor
NRSE = Neuron restrictive silencer element
NRSF = Neuron restrictive silencer factor
ODNs = Oligodeoxynucleotides
QA = Quinolinic acid
REST= Repressor element-1 transcription factor
SAHA = Suberoylanilide hydroxamic acid
Sp 1= Specificity protein 1
TAF = TBP-associated factor
TATA = Adenine- and thymine-rich promoter sequence
TBP = TATA box binding protein
cell proliferation and
The mechanistic insights described during the last years
suggest different therapeutic approaches aiming at each of the
cellular targets that contribute to HD pathogenesis, namely
by: i) blocking excitotoxicity with NMDA antagonists; ii)
improving the energetic state through metabolic enhancers;
iii) blocking proteolysis and/or apoptosis with caspase
inhibitors; iv) interfering
transglutaminase inhibitors; v) reducing mutant huntingtin
toxicity with chaperones or disaccharides; vi) upregulating
transcription by inhibiting histone deacetylases; vii)
silencing mutant huntingtin expression; or viii) replacing
lesioned neurons by transplantation of neural stem cells.
Moreover, an active investigation in polyglutamine
expansion diseases will bring about new molecular targets
not only for HD therapy, but also for the cure of other
neurodegenerative diseases. While some of the therapies
against HD pathogenesis are still under experimental
analysis or taking the first steps into clinical trials, an
exhaustive study of combination therapies is required both
in in vitro and in vivo HD models.
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LIST OF ABBREVIATIONS
3-NP= 3-nitropropionic acid
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