Current status of treatment of spinal and bulbar muscular atrophy.
ABSTRACT Spinal and bulbar muscular atrophy (SBMA) is the first member identified among polyglutamine diseases characterized by slowly progressive muscle weakness and atrophy of the bulbar, facial, and limb muscles pathologically associated with motor neuron loss in the spinal cord and brainstem. Androgen receptor (AR), a disease-causing protein of SBMA, is a well-characterized ligand-activated transcription factor, and androgen binding induces nuclear translocation, conformational change and recruitment of coregulators for transactivation of AR target genes. Some therapeutic strategies for SBMA are based on these native functions of AR. Since ligand-induced nuclear translocation of mutant AR has been shown to be a critical step in motor neuron degeneration in SBMA, androgen deprivation therapies using leuprorelin and dutasteride have been developed and translated into clinical trials. Although the results of these trials are inconclusive, renewed clinical trials with more sophisticated design might prove the effectiveness of hormonal intervention in the near future. Furthermore, based on the normal function of AR, therapies targeted for conformational changes of AR including amino-terminal (N) and carboxy-terminal (C) (N/C) interaction and transcriptional coregulators might be promising. Other treatments targeted for mitochondrial function, ubiquitin-proteasome system (UPS), and autophagy could be applicable for all types of polyglutamine diseases.
- Neurology 08/1968; 18(7):671-80. · 8.25 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Expansion of polyglutamine tracts in nine different genes causes selective neuronal degeneration through unknown mechanisms. Expansion of polyglutamine in the androgen receptor is responsible for spinal and bulbar muscular atrophy (SBMA), a neuromuscular disorder characterized by the loss of lower motor neurons in the brainstem and spinal cord. A unique feature of SBMA in the family of polyglutamine diseases is sex specificity. SBMA fully manifests only in males. SBMA is a disease triggered by the binding of polyglutamine androgen receptor to its natural ligand testosterone. Recent evidence has emerged showing that the expanded polyglutamine tract itself is not the only determinant of disease pathogenesis. There is evidence that both the native structure and function of the disease protein strongly influence the pathogenicity of mutant protein. Here, we review recent progress in the understanding of disease pathogenesis and advancements towards development of potential therapeutic strategies for SBMA.Frontiers in Neuroendocrinology 07/2011; 32(4):416-25. · 7.99 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.Nature 08/1991; 352(6330):77-9. · 38.60 Impact Factor
Hindawi Publishing Corporation
Volume 2012, Article ID 369284, 8 pages
CurrentStatus of Treatmentof Spinal andBulbar
FumiakiTanaka,Masahisa Katsuno,HaruhikoBanno, KeisukeSuzuki,
Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Correspondence should be addressed to Fumiaki Tanaka, firstname.lastname@example.org
Received 5 March 2012; Accepted 18 April 2012
Academic Editor: Hansen Wang
Copyright © 2012 Fumiaki Tanaka et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Spinal and bulbar muscular atrophy (SBMA) is the first member identified among polyglutamine diseases characterized by slowly
progressive muscle weakness and atrophy of the bulbar, facial, and limb muscles pathologically associated with motor neuron loss
in the spinal cord and brainstem. Androgen receptor (AR), a disease-causing protein of SBMA, is a well-characterized ligand-
activated transcription factor, and androgen binding induces nuclear translocation, conformational change and recruitment of
coregulators for transactivation of AR target genes. Some therapeutic strategies for SBMA are based on these native functions of
AR. Since ligand-induced nuclear translocation of mutant AR has been shown to be a critical step in motor neuron degeneration
in SBMA, androgen deprivation therapies using leuprorelin and dutasteride have been developed and translated into clinical
trials. Although the results of these trials are inconclusive, renewed clinical trials with more sophisticated design might prove the
effectiveness of hormonal intervention in the near future. Furthermore, based on the normal function of AR, therapies targeted
for conformational changes of AR including amino-terminal (N) and carboxy-terminal (C) (N/C) interaction and transcriptional
coregulators might be promising. Other treatments targeted for mitochondrial function, ubiquitin-proteasome system (UPS), and
autophagy could be applicable for all types of polyglutamine diseases.
Spinal and bulbar muscular atrophy (SBMA) was first
described in 1897 by a Japanese neurologist, Kawahara ,
and has been known worldwide as Kennedy’s disease since
degeneration and loss of lower motor neurons in the brain-
wasting of the facial, bulbar, and limb muscles, along with
sensory disturbances and endocrinological abnormalities [3,
caused by an abnormal expansion of tandem CAG repeat in
exon 1 of the androgen receptor (AR) gene on chromosome
Xq11-12 . In normal individuals, the CAG repeat ranges
in size between 9 and 36, and expansion over 38 and up
to 62 is pathogenic [5, 6]. Polyglutamine-expanded mutant
AR accumulates in nuclei, undergoes fragmentation, and
initiates degeneration and loss of motor neurons [7, 8].
So far, nine polyglutamine diseases are known including
SBMA, Huntington’s disease, dentatorubral-pallidoluysian
atrophy, and six forms of spinocerebellar ataxia (SCA),
known as SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17
[9, 10]. These diseases share several features such as late-
onset, progressive neurodegeneration, anticipation, somatic
mosaicism, and accumulation of misfolded mutant proteins
in the nuclei or cytoplasm of neurons [8–13]. Expanded
polyglutamine tracts form antiparallel beta-strands held
together by hydrogen bonds formed between the main chain
of one strand and the side chain of the adjacent strand.
This leads the polyglutamine protein to acquire a nonnative
beta-sheet conformation, which results in the accumulation
of misfolded protein into microaggregates/oligomers and
protein into inclusions is considered to be protective [15–
17], while diffuse nuclear microaggregates/oligomers might
be toxic . These aggregates and inclusions contain
components of the ubiquitin proteasome system (UPS) and
molecular chaperons, which attempt to degrade or refold the
features of aggregates and inclusions observed in polyglu-
tamine diseases suggest that the expanded polyglutamine
tract itself seems to be deeply involved in the pathogenesis.
However, the observation that the same genetic mutation
in nine different proteins results in nine different diseases
highlights both the significance of a specific protein context
other than the polyglutamine tract and the role of normal
protein function in the pathogenesis of polyglutamine
diseases . Direct evidence that native protein functions
and interactions may mediate toxicity comes from an animal
model in which overexpression of wildtype AR harbor-
ing nonexpanded polyglutamine tract results in pathology
eases, neither the primary function nor the native interactors
of the disease proteins are well known. SBMA represents an
exception because AR protein structure and function as a
ligand-dependent transcription factor are well characterized.
AR belongs to the family of steroid hormone receptors and
is composed of an amino-terminal domain, a DNA-binding
domain, and a ligand-binding domain . In the inactive
shock proteins (HSPS). Testosterone binding to AR leads to
the dissociation of AR from Hsps and causes nuclear translo-
cation (Figure 1) [3, 23]. Also, ligand binding induces con-
formational changes of AR such as intra- or inter-molecular
amino/carboxy-terminal (N/C) interactions (Figure 1) [3,
24]. Nuclear translocation of AR is followed by DNA binding
to androgen-responsive elements, which in turn leads to
recruitment of coregulators and expression regulation of
androgen-responsive genes (Figure 1). These native func-
tions and sequential processing of AR have important roles
for the pathogenesis and therapy development of SBMA.
In SBMA, expanded polyglutamine tracts are associated
to lower levels of transcription of androgen-responsive genes
[25, 26], which in turn lead to mild androgen insensitivity
symptoms such as gynecomastia, feminized skin changes,
testicular atrophy, and oligospermia/azoospermia causing
reduced fertility . However, dysregulation of androgen-
responsive genes does not likely contribute to the neurologi-
cal symptoms of SBMA, because complete androgen insensi-
tivity syndrome associated with total loss of AR function has
no signs of neurodegeneration , and AR knock out mice
are also normal in motor neuron functions .
So far, therapeutic interventions have been developed
to target a number of events occurring through native AR
been established in SBMA, this review illustrates several
therapeutic strategies based on the native function of AR and
the common mechanisms shared by polyglutamine diseases.
2.Therapeutic Interventions to Inhibit Nuclear
Due to the X-linked transmission, SBMA exclusively affects
males and is transmitted by clinically unaffected or mildly
manifesting female carriers. A unique gender-specific feature
of SBMA is well recapitulated in both vertebrate and inver-
tebrate animal models of the disease [30, 31]. In transgenic
mice expressing polyglutamine-expanded mutant AR, the
disease fully manifests only in males due to higher levels
of circulating androgens [30, 32, 33]. Importantly, decrease
of androgen levels by castration of transgenic male mice
prevents neurodegeneration, while treatment of transgenic
female mice with testosterone induces disease manifestations
. In a fly model of SBMA, neurodegeneration occurs
only if the flies are reared in a hormone-containing food
, further supporting the ligand-dependent neurotoxicity
of pathogenic AR. The prerequisite for SBMA pathogenesis
is both the existence of ligand and nuclear translocation of
mutant AR. This is shown by the observation that cyto-
plasmic retention of mutant AR by deletion of the nuclear
localization signal suppresses polyglutamine-AR toxicity in
SBMA mouse model .
Leuprorelin is a potent luteinizing hormone-releasing
hormone analog that decreases the production of testos-
terone and its more potent derivative, dihydrotestosterone
(DHT), and has been used for the treatment of a variety of
sex hormone-dependent diseases including prostate cancer,
endometriosis, and central precocity . Treatment of
SBMA mice with leuprorelin reduced both polyglutamine-
AR nuclear aggregation and inclusion formation in spinal
cord as well as skeletal muscle and reversed the behavioral
and histopathological phenotypes (Figure 1) . These
dramatic therapeutic effects of leuprorelin observed in a
trial, and the patients treated with leuprorelin for 144 weeks
exhibited significantly greater functional scores and better
swallowing parameters than those who received a placebo
. Leuprorelin significantly diminished the serum level
of creatine kinase and decreased mutant AR accumulation
in scrotal skin of treated patients . Of note, leuprorelin
inhibited the nuclear accumulation and/or stabilization of
mutant AR in the motor neurons of the spinal cord and
brainstem of an autopsied patient who received it for 2 years
. More recently, a larger randomized placebo-controlled
multicentric clinical trial of this drug showed no definite
effect on motor functions, although swallowing function
improved in a subgroup of patients whose disease duration
was less than 10 years .
Another potent drug for hormonal intervention is the
5-α-reductase inhibitor, dutasteride. The observation that
motor neurons degenerating in SBMA express high levels of
5-α-reductase suggests that the conversion of testosterone to
DHT represents a potential therapeutic target (Figure 1) .
However, the effectiveness of dutasteride was not proven in a
primary outcome measure of quantitative muscle assessment
Although the results of these clinical trials are inconclu-
sive, their findings do not exclude the possibility that ligand-
targeted hormonal therapies slow the progression of SBMA.
leuprorelin, a 75-year-old male SBMA patient who received
leuprorelin for 5 years due to coexisting prostate cancer was
Possible therapeutic targets
Figure 1: Potential disease-modifying therapies for spinal and bulbar muscular atrophy (SBMA). Ligand-induced nuclear translocation of
mutant androgen receptor (AR) is a critical step of motor neuron degeneration in SBMA. In order to block this step, androgen deprivation
therapies using leuprorelin and dutasteride have been developed. AR phosphorylation is another potential treatment strategy through
attenuation of ligand binding. Insulin-like growth factor-1 (IGF-1) reduces mutant AR toxicity through phosphorylation of AR at the Akt
consensus sites. Amino-terminal (N) and carboxy-terminal (C) (N/C) interaction of mutant AR is critical for toxicity, and this interaction
is blocked by selective AR modulators such as RTI-016 and RTI-051b. The SBMA modifier melatonin blocks toxic fibrillar and induces
nontoxic annular aggregates. As a transcription factor, the binding of AR to DNA in the nucleus is followed by the recruitment of a
variety of transcriptional coregulators. 5-Hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction
between AR and its coregulators and yields a therapeutic effect. In SBMA, histone acetylation is impaired, resulting in transcriptional
dysregulation. Sodium butyrate, histone deacetylase (HDAC) inhibitor is effective at this step. Furthermore, transcriptionally attenuated
genes such as vascular endothelial growth factor (VEGF), dynactin-1, and transforming growth factor β receptor type II (TGF-βRII)
are also possible therapeutic targets. Decreased expression of peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) is one
of the causes of mitochondrial dysfunction, and treatments with the antioxidants coenzyme Q10 and idebenone have been developed
targeting mitochondria. Mutant AR is degraded through induction of the ubiquitin-proteasome system (UPS) by acyclic isoprenoid
geranylgeranylacetone (GGA) and heat shock protein 90 (Hsp90) inhibitors such as 17-(allylamino)-17-demethoxygeldanamycin (17-AAG)
and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG). Autophagy induction using rapamycin and trehalose is also
effective for AR degradation in fly and cell models of SBMA. However, the opposite results concerning autophagy augmentation therapy
were recently reported in SBMA knock-in mice.
reported to show long-term stabilization of motor function
even when the treatment was started in the advanced stage of
the disease .
Besides the hormonal interventions, attenuation of lig-
and binding might be another therapeutic strategy for
inhibition of nuclear transport of mutant AR. Ligand
binding is at least partly mediated by phosphorylation of
the mutant AR. Interestingly, substitution of the AR at
two Akt consensus sites, S215 and S792, with aspartate,
which mimics phosphorylation, reduces ligand binding,
vation, and toxicity of expanded polyglutamine AR .
Furthermore, in motor neuron-derived MN-1 cells toxicity
associated with polyglutamine-expanded, AR is rescued by
coexpression with Akt . Insulin-like growth factor-
1 (IGF-1) reduces mutant AR toxicity in cultured cells
through phosphorylation of AR at the Akt consensus sites
. Interestingly, augmentation of IGF-1/Akt signaling by
overexpressing a muscle-specific isoform of IGF-1 selectively
in skeletal muscle ameliorated the neurological phenotypes,
extended the life span, and rescued not only muscle but
also spinal cord pathology of SBMA transgenic mice .
This finding also indicates skeletal muscle as a viable target
tissue for therapeutic intervention in SBMA. These results
for therapeutic intervention through inhibition of nuclear
transport of mutant AR in SBMA (Figure 1).
3.Therapy Targeted for Conformational
Changes of AndrogenReceptor (AR) and
Ligand-mediated nuclear localization of the mutant AR is
necessary but not sufficient for SBMA pathogenesis. Upon
ligand binding, the AR undergoes several conformational
changes including the interdomain interaction between
the 23FQNLF27 motif near the amino terminus and the
activation function-2 (AF2) domain near the ligand-bound
carboxyl terminus (N/C interaction) [42, 43]. This N/C
interaction is critical for toxicity through stabilizing the
AR and enhancing hormone binding [44, 45]. Selective
androgen receptor modulators such as RTI-016 and RTI-
051b prevent the N/C interaction and ameliorated AR
aggregation and toxicity while retaining AR transcriptional
function, highlighting a novel therapeutic strategy for SBMA
(Figure 1) .
Another strategy for reducing toxicity of mutant AR is
based on alteration of the morphology of the oligomers.
Recently, Jochum and colleagues demonstrated that the
pathogenic AR mutants formed oligomeric fibrils up to
300–600nm in length, whereas annular oligomers 120–
180nm in diameter were formed by the nonpathogenic
receptors . They showed that melatonin ameliorated the
pathological phenotype of the SBMA fly model through
the conformational change of the polyglutamine-expanded
oligomers from the toxic fibrillar forms to nontoxic annular
forms (Figure 1) .
As a ligand-dependent transcription factor, the binding
of AR to DNA is followed by the recruitment of a variety of
transcriptional coregulators, both coactivators and corepres-
sors of transcription [47, 48]. In most steroid receptors, AF-2
ing as the interaction surface for transcriptional coregulators
. K720A and E897K mutations to the AF-2 attenuated
polyglutamine-expanded AR toxicity in a Drosophila model
of SBMA , suggesting that this toxicity requires DNA
binding followed by association with coregulators through
the AF-2 domain. In motor neurons, one of the key AR
binding protein (CBP), a transcriptional coactivator for neu-
ronal survival factors . In SBMA, through the sequestra-
tion of CBP by expanded polyglutamine aggregates [49, 50],
limiting levels of CBP, resulting in transcriptional distur-
bance. These observations raise the possibility of a therapeu-
1,4,6-heptatrien-3-one (ASC-J9). ASC-J9 disrupts the inter-
action between AR and its coregulators including ARA70
and CBP (Figure 1) and markedly ameliorates phenotypes of
SBMA transgenic mice by decreasing mutant AR aggregation
. ASC-J9 did not change the serum testosterone level in
contrast to hormonal therapies associated with reduction of
testosterone causing side effects on sexual functions.
CBP exerts its transcriptional coactivating function
through histone acetyltransferase (HAT) activity. Overex-
pression of CBP rescued histone acetylation and neurode-
generation in cell and animal models of SBMA [50, 52] in
association with subsequent restoration of gene transcrip-
tion, whereas histone deacetylase (HDAC) inhibitor also
acetylates histone, suggesting that it may be of therapeutic
value. Oral administration of sodium butyrate, an HDAC
inhibitor, ameliorated neurological phenotypes as well as
increased acetylation of nuclear histone in neural tissues of
a mouse model of SBMA (Figure 1) . Beneficial effects
of this compound, however, were seen within a narrow
therapeutic window of dosage.
Downstream targets associated with decreased expres-
sion through transcriptional dysregulation in SBMA include
vascular endothelial growth factor (VEGF), dynactin-1, and
transforming growth factor β (TGF-β) receptor type II [54–
57]. The importance of VEGF on maintenance of motor
neuron is highlighted by motor neuron loss in mice with
a homozygous deletion in the hypoxia-response element
site in the VEGF promoter region . Moreover, mutant
AR-induced death of motor neuron-like cells (MN-1 cells)
could be rescued by VEGF supplementation . Dynactin-
1 is a critical component of dynein/dynactin complex, a
microtubule motor protein essential for retrograde axonal
transport [59, 60], and its mutation was identified as the
cause of a slowly progressive, autosomal dominant form of
lower motor neuron disease . In the mouse model of
SBMA, pathogenic AR impairs retrograde axonal transport
via transcriptional dysregulation of dynactin-1 . TGF-
β signaling was demonstrated to play a crucial role in the
survival and function of adult neurons . Transcriptional
inhibition of TGF-β receptor type II suppressed nuclear
translocation of phosphorylated Smad2/3, a key step in TGF-
β signaling in the spinal motor neurons of SBMA mice and
transcriptionally dysregulated molecules might be another
effective therapeutic approach (Figure 1).
4.Therapy Targeted for Ubiquitin-Proteasome
System(UPS)and Autophagy System
The two major intracellular mechanisms for the degradation
of misfolded proteins are the ubiquitin-proteasome system
(UPS) and lysosome-mediated autophagy . The degra-
dation and removal of mutant AR may be obtained through
overexpressing different Hsps, such as Hsp40 and Hsp70
through UPS pathway [63–65]. Moreover, the C-terminus of
heat shock protein 70 interacting protein (CHIP) interacts
with hsp90 or hsp70 and ubiquitylates misfolded proteins
trapped by molecular chaperones and degrades them [19,
66]. Similar effects can also be induced by oral administra-
tion of the acyclic isoprenoid geranylgeranylacetone (GGA)
. GGA increased the levels of expression of Hsp70,
Hsp90, and Hsp105, leading to inhibition of cell death,
and amelioration of the neuromuscular phenotype of SBMA
mice via activation of heat shock factor-1 and reduction
of nuclear accumulation of polyglutamine-expanded AR
(Figure 1) .
In addition, Hsp90 inhibitors are able to promote the
clearance of Hsp90 client proteins including misfolded mu-
tant AR through the UPS. Treatment with potent Hsp90
anamycin (17-AAG) or its derivative 17-(dimethylaminoeth-
hanced proteasomal degradation of the monomeric and
aggregated mutant AR, reduced motor neuron degeneration,
and increased survival in SBMA mice (Figure 1) [68–70].
It is to be noted that 17-AAG also disrupts the interaction
between hsp90 and other client proteins, including steroid
receptors, such as glucocorticoid receptor (GR), estrogen
receptor-α (ERα), and retinoid X receptor-α (RXRα) ,
rendering them more susceptible to degradation and leading
to unwanted side effects. Interestingly, a recent report
shows that in motor neuron-derived cells 17-AAG removes
misfolded AR species and aggregates by activating the
autophagy system rather than UPS .
This report indicates the importance of link and equilib-
rium between these two degradative systems . In partic-
ular, HDAC6 plays an important role in the functional rela-
tionship between UPS and autophagy . Compensatory
autophagy is induced in response to UPS impairment in
the SBMA fly model in an HDAC6-dependent manner .
Furthermore, HDAC6 overexpression rescued degeneration
associated with UPS dysfunction accelerating the rate of
mutant AR clearance through autophagy .
Other therapeutic approaches to augment autophagy
induction are the use of rapamycin, an mTOR inhibitor ,
in SBMA mouse suggests that autophagy activators are
unlikely to be effective therapeutics for the subset of protein
aggregation disorders such as SBMA where nuclear local-
ization of the mutant protein is required for toxicity .
This suggests the need for due care in the use of autophagy
Mitochondrial dysfunction has been implicated in various
neurodegenerative diseases, including Huntington’s disease,
amyotrophic lateral sclerosis and Friedreich’s ataxia [76,
77]. Expression of the mutant AR in cell cultures results
in depolarization of the mitochondrial membrane and an
elevated level of reactive oxygen species, which is blocked
by treatments with the antioxidants coenzyme Q10 and
idebenone (Figure 1) . Mitochondrial dysfunction in
SBMA is caused either by the indirect effects on the
transcriptional repression of nuclear-encoded mitochon-
drial genes such as the peroxisome proliferator-activated
receptor-γ-coactivator 1 (PGC-1) (Figure 1) and the mito-
chondrial specific antioxidant superoxide dismutase 2 or
through direct effects of the mutant protein on mitochon-
dria or both . Therapeutic interventions targeted for
mitochondrial function, UPS, or autophagy system might
be promising treatments for all types of polyglutamine
SBMA is the first identified member of nine polyglutamine
diseases , and due to its advantages through the well-
investigated disease-causing protein structure and func-
tion, it has a leading place among polyglutamine diseases,
especially from the standpoint of development of disease-
modifying treatment as represented by hormonal thera-
pies. However, despite dramatic efficacy in animal studies,
hormonal therapies are not successfully translated into the
clinical field at present [37, 38]. In consideration of the
limited availability of participants, together with the slow
progression of symptoms, clinical trials of SBMA should
be carefully designed in terms of endpoints, sample size,
than hormonal therapies, therapeutic strategies have been
developed to target many steps of the exertion of mutant AR
toxicity as described in this article. It is possible that together
with hormonal therapy preventing nuclear translocation of
mutant AR, additional therapies targeted for the molecular
events occurring after this translocation will strengthen the
therapeutic effect for SBMA.
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