Article

Orr HT, Zoghbi HY. Trinucleotide repeat disorders

Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Annual Review of Neuroscience (Impact Factor: 19.32). 02/2007; 30(1):575-621. DOI: 10.1146/annurev.neuro.29.051605.113042
Source: PubMed
ABSTRACT
The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.

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ANRV314-NE30-22 ARI 20 May 2007 16:10
Trinucleotide Repeat
Disorders
Harry T. Orr
1
and Huda Y. Zoghbi
2
1
Institute of Human Genetics, Department of Laboratory Medicine and Pathology,
University of Minnesota, Minneapolis, Minnesota, 55455; email: orrxx002@umn.edu
2
Departments of Pediatrics, Molecular and Human Genetics, Neurology, and
Neuroscience, Baylor College of Medicine, and Howard Hughes Medical Institute,
Houston, Texas 77030; email: hzoghbi@bcm.edu
Annu. Rev. Neurosci. 2007. 30:575–621
First published online as a Review in Advance on
April 6, 2007
The Annual Review of Neuroscience is online at
neuro.annualreviews.org
This article’s doi:
10.1146/annurev.neuro.29.051605.113042
Copyright
c
2007 by Annual Reviews.
All rights reserved
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Key Words
unstable repeats, ataxia, Huntington disease, fragile X syndrome,
mental retardation, myotonic dystrophy, spinal bulbar muscular
atrophy, ataxin, frataxin, polyglutamine
Abstract
The discovery that expansion of unstable repeats can cause a vari-
ety of neurological disorders has changed the landscape of disease-
oriented research for several forms of mental retardation, Hunting-
ton disease, inherited ataxias, and muscular dystrophy. The dynamic
nature of these mutations provided an explanation for the variable
phenotype expressivity within a family. Beyond diagnosis and ge-
netic counseling, the benefits from studying these disorders have
been noted in both neurobiology and cell biology. Examples include
insight about the role of translational control in synaptic plasticity,
the role of RNA processing in the integrity of muscle and neuronal
function, the importance of Fe-S-containing enzymes for cellular
energy, and the dramatic effects of altering protein conformations
on neuronal function and survival. It is exciting that within a span of
15 years, pathogenesis studies of this class of disorders are beginning
to reveal pathways that are potential therapeutic targets.
575
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Contents
INTRODUCTION................. 576
DISEASES CAUSED BY
LOSS OF PROTEIN
FUNCTION .................... 577
Fragile X Syndrome .............. 577
Fragile XE Syndrome............. 581
Friedreich Ataxia ................. 582
DISEASES CAUSED BY
RNA-MEDIATED
GAIN-OF-FUNCTION
MECHANISM .................. 584
Myotonic Dystrophy ............. 584
Fragile X–Associated
Tremor Ataxia Syndrome
(FXTAS) ...................... 587
DISORDERS CAUSED BY
GAIN-OF-FUNCTION
MECHANISM:
POLYGLUTAMINE
DISORDERS .................... 588
Spinobulbar Muscular Atrophy.... 588
Huntington Disease .............. 589
The Spinocerebellar Ataxias....... 589
STUDIES OF POLYGLUTAMINE
DISORDERS .................... 590
Introductory Comments .......... 590
SBMA: A Nuclear
Receptor-Mediated
Neurodegenerative Disease .... 590
The Multiple Pathogenic Pathways
ofHD........................ 592
SCA1: Corepressors/Coactivators
and Neurodegenerative
Disease ....................... 596
SCA2: A Disease of RNA
Metabolism ................... 599
SCA3 and Regulation of
Ubiquitin-Proteasome
Mediated Degradation ......... 599
SCA6: A Membrane Calcium
Channel and Transcription
Regulation .................... 600
SCA7: Chromatin Structure and
Neurodegeneration............ 601
SCA17: Neurodegeneration and
the TATA-Box Binding
Protein ....................... 602
DRPLA: Transcription
Corepressor Dysfunction ...... 602
DISEASES LACKING A CLEAR
PATHOGENIC MECHANISM. . 603
CONCLUSIONS................... 604
Ataxia: inability to
coordinate
movements
Anticipation: when
age of onset is earlier
and disease severity
increases in
successive
generations
INTRODUCTION
The discovery that expansion of unstable trin-
ucleotide repeats can cause neurological dis-
orders (Fu et al. 1991, La Spada et al. 1991)
provided the first evidence that not all disease-
causing mutations are stably transmitted from
parent to offspring. Moreover, the discovery
of these dynamic mutations provided a molec-
ular explanation for the variability in expres-
sivity or severity of the disease phenotype:
the larger the expansion, the earlier the on-
set and the more severe the course. Trinu-
cleotide repeat expansions now account for at
least 16 neurological disorders ranging from
developmental childhood disorders such as X-
linked mental retardation syndromes to the
late onset neurodegenerative disorders such
as Huntington disease and the inherited atax-
ias. The variability in repeat size underlies
the broad spectrum of phenotypes seen in
each of these disorders. The repeats show
somatic and germline instability. Successive
generations of families affected by such dy-
namic mutations experience anticipation or
earlier age of onset and more rapid disease
progression owing to intergenerational re-
peat instability. For example, the onset of
the neuromuscular disorder myotonic dys-
trophy ranges from birth in children and
grandchildren to adulthood in parents and
grandparents, depending on the size of the
repeat.
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Table 1 Unstable repeat disorders caused by loss-of-function, RNA-mediated, or unknown mechanism
Disease
MIM
Number
Repeat
unit
Gene
product
Normal
repeat
Expanded
repeat
Main clinical features length
Loss of function mechanism
FRAXA 309550 (CGC)
n
FMRP 6–60 >200 (full
mutation)
Mental retardation, macroorchidsm,
connective tissue defects, behavioral
abnormalities
FRAXE 309548 (CCG)
n
FMR2 4–39 200–900 Mental retardation
FRDA 229300 (GAA)
n
Frataxin 6–32 200–1700 Sensory ataxia, cardiomyopathy, diabetes
RNA-mediated pathogenesis
DM1 160900 (CTG)
n
DMPK 5–37 50–10,000 Myotonia, weakness, cardiac conduction
defects, insulin resistance, cataracts,
testicular atrophy, and mental retardation
in congenital form
DM2 602668 (CCTG)
n
ZNF9 10–26 75–11,000 Similar to DM1 but no congenital form
FXTAS 309550 (CGG)
n
FMR1 RNA 6–60 60–200
(premutation)
Ataxia, tremor, Parkinsonism, and
dementia
Unknown pathogenic mechanism
SCA8 608768 (CTG)
n
SCA8 RNA 16–34 >74 Ataxia, slurred speech, nystagmus
SCA10 603516 (ATTCT)
n
10–20 500–4500 Ataxia, tremor, dementia
SCA12 604326 (CAG)
n
PPP2R2B 7–45 55–78 Ataxia and seizures
HDL2 606438 (CTG)
n
Junctophilin 7–28 66–78 Similar to HD
Although unstable trinucleotide repeats
are the most common repeats to cause
neurological disorders, other repeats such
as tetra- and pentanucleotides expand to
cause type 2 myotonic dystrophy and ataxia,
respectively.
Several developmental and neuromuscu-
lar disorders are caused by either an inser-
tion or a duplication of a small trinucleotide
repeat (GCG)
n
typically encoding alanine.
Examples of such disorders include hand-
foot-genital syndrome, synpolydactyly, ocu-
lopharyngeal muscular dystrophy, and the
X-linked mental retardation caused by muta-
tions in the Aristaless-related homeobox gene
(Brais et al. 1998, Stromme et al. 2002, Utsch
et al. 2002). These disorders differ from the
classic trinucleotide repeat expansion disor-
ders because the expansions are small and are
not as dynamic. In this review, we focus on
trinucleotide, tetranucleotide, and pentanu-
cleotide repeat disorders caused by unstable
expansions rather than insertions or duplica-
tion. Tables 1 and 2 provide a concise descrip-
tion of these disorders, the mutational basis,
the gene product, and key clinical features.
The disorders have been divided according
to pathogenic mechanism, i.e., whether mu-
tations cause loss of function of the protein
or gain of function of the RNA or protein
or cause a yet-to-be-determined mechanism.
The more detailed discussion in the text is
structured to discuss the clinical features and
molecular basis of each disorder, followed by
a discussion of pathogenesis according to a
mechanism-based classification.
DISEASES CAUSED BY LOSS
OF PROTEIN FUNCTION
Fragile X Syndrome
Clinicopathology. In 1943, Martin & Bell
(1943) described a family in which mental re-
tardation segregated as an X-linked trait. Lubs
(1969) observed and reported on a constric-
tion on the long arm of the X chromosome
in some mentally retarded males. Harrison
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Table 2 Polyglutamine disorders
a
caused by a gain-of-function mechanism
Disease
MIM
number
Gene
product
Normal repeat
length
Expanded
repeat length
Main clinical features
HD 143100 Huntingtin 6–34 36–121 Chorea, dystonia, cognitive deficits, psychiatric
problems
SCA1 164400 Ataxin1 6–44
b
39–82 Ataxia, slurred speech, spasticity, cognitive
impairments
SCA2 183090 Ataxin2 15–24 32–200 Ataxia, polyneuropathy, decreased reflexes, infantile
variant with retinopathy
SCA3 109150 Ataxin3 13–36 61–84 Ataxia, parkinsonism, spasticity
SCA6 183086 CACNA1
A
4–19 10–33 Ataxia, dysarthria, nystagmus, tremors
SCA7 164500 Ataxin7 4–35 37–306 Ataxia, blindness, cardiac failure in infantile form
SCA17 607136 TBP 25–42 47–63 Ataxia, cognitive decline, seizures, and psychiatric
problems
SBMA 313200 Androgen
receptor
9–36 38–62 Motor weakness, swallowing, gynecomastia,
decreased fertility
DRPLA 125370 Atrophin 7–34 49–88 Ataxia, seizures, choreoathetosis, dementia
a
The repeat unit is (CAG)
n
in all these disorders.
b
Normal SCA1 alleles 21 CAG repeats are interrupted with 1–2 CAT units, whereas disease-causing alleles are pure (CAG)
n
.
FRAXA: fragile X
syndrome
UTR: untranslated
region
Premutation:
repeat length that
rarely causes a
disease but that is
likely to expand to
disease-causing
mutation length in
successive
generations
and colleagues (1983) mapped this chromo-
somal variation to Xq27.3 and dubbed it “the
fragile X chromosome.” Cytogenetic studies
eventually linked this fragile site to the men-
tal retardation in families who became known
to have “the fragile X syndrome” (Richards
et al. 1981, Sutherland 1977). Fragile X syn-
drome (FRAXA) occurs in 1 in 4000 males
and 1 in 8000 females (Turner et al. 1996).
Affected males have moderate-to-severe men-
tal retardation, speech delay, and a variety
of behavioral and social problems. They are
often hyperactive and anxious. Many fragile
X males display features of autism including
gaze avoidance, stereotyped repetitive move-
ments, and resistance to change in their rou-
tines or environments. In addition to neu-
ropsychiatric features, patients display several
somatic features including macroorchidism
and connective tissue abnormalities such as
hyperextensibility of joints and large ears
(Hagerman et al. 1984). About one third of
females have some intellectual disability.
Postmortem neuropathological studies re-
vealed dendritic abnormalities in the neurons
of affected males, including abnormal spine
shapes and numbers in the parieto-occipital
cortex (Irwin et al. 2001). Specifically, frag-
ile X syndrome patients showed an increase
in long spines and a decrease in short spines
compared with controls. The long spines
had immature morphology, and spine den-
sity was high on apical and basilar dendrites
reminiscent of cortex features during early
development.
Mutation and gene product. The gene re-
sponsible for fragile X syndrome is FMR1,
which encodes the protein FMRP. The mu-
tational mechanism in most cases is an expan-
sion of an unstable noncoding CGG repeat
in the 5
untranslated region (UTR) of FMR1
(Fu et al. 1991, Warren & Sherman 2001).
Normal alleles contain 6–55 repeats, premu-
tation alleles contain 55–200, and fragile X–
causing alleles have >200 repeats. The dis-
covery of the gene allowed better phenotype-
genotype studies on extended fragile X fam-
ilies and revealed that males (and to a lesser
degree females) with the premutation alle-
les developed a late-onset neurodegenerative
disorder termed fragile X-associated tremor/
ataxia syndrome (see below) (Hagerman
& Hagerman 2004a,b). Approximately one
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fourth of females carrying a premutation allele
develop ovarian failure (Allingham-Hawkins
et al. 1999). The repeat expansion in the full
mutation range causes aberrant methylation
of CpG island in the 5
regulatory region of
FMR1 (Verkerk et al. 1991). This increased
methylation coupled with decreased histone
acetylation (Coffee et al. 1999) at the 5
of
the gene led to loss of FMR1 expression and
FMRP function. FMRP is a selective RNA-
binding protein that contains two KH do-
mains (KH1 and KH2; add 1) and an RGG
box (Siomi et al. 1993). It is predominantly cy-
toplasmic, but it shuttles between the nucleus
and the cytoplasm. It associates with polyribo-
somes in an RNA-dependant manner through
messenger ribonucleoprotein (mRNP) par-
ticles to control local protein synthesis by
suppressing the translation of the mRNAs it
binds. Consistent with this function, a point
mutation in the KH2 domain abolishes asso-
ciation with polyribosomes and causes fragile
X syndrome (Feng et al. 1997, Laggerbauer
et al. 2001, Li et al. 2001).
Pathogenesis studies. Insight about the
pathogenesis of the fragile X syndrome is
emerging from both biochemical and molec-
ular studies as well as in vivo behavioral and
physiological studies of animal models. Mouse
models lacking Fmrp have been generated us-
ing gene targeting by homologous recombi-
nation. Fmr1 null mice reproduce many of the
physical and behavioral features of the fragile
X syndrome including macroorchidism, hy-
peractivity, anxiety-related behaviors, motor
incoordination, and cognitive deficits (Bakker
et al. 1994, Brennan et al. 2006, D’Hooge et al.
1997, Dobkin et al. 2000, Mineur et al. 2002,
Paradee et al. 1999, Peier et al. 2000, Ventura
et al. 2004). It is quite interesting that the
dendritic and spine abnormalities seen in pa-
tients are also evident in the mice and that the
eye-blink conditioning response that is im-
paired in patients is also impaired in a con-
stitutive as well as Purkinje cell–specific dele-
tion of Fmr1 (Irwin et al. 2002, Koekkoek
et al. 2005). Given the association of FMRP
KH domain: K
homology (KH)
domain, a domain
that binds RNA, was
first identified in the
human
heterogeneous
nuclear
ribonucleprotein K
RGG box: motif
that binds RNA and
consists of short
arginine- and
glycine-rich
sequences
with polyribosomes and its ability to bind
mRNAs, FMRP likely regulates the transla-
tion of its RNA targets. This indeed proved
to be the case (Brown et al. 2001). FMRP asso-
ciates with different classes of mRNA through
different domains. The RGG box of FMRP
binds to an RNA class that contains G quar-
tets, a secondary structure formed in RNA
when four consecutive guanosine residues
bind to each other and form an intramolecular
stem loop (Darnell et al. 2001, Schaeffer et al.
2001). The KH2 domain recognizes a more
intricate tertiary structure in RNA targets
termed the FMRP-kissing complex (Darnell
et al. 2005). Among the targets identified,
several are involved in cytoskeletal structure,
synaptic transmission, and neuronal matura-
tion. Mice that lack Fmrp have increased rates
of protein synthesis of the targets (Qin et al.
2005). It is interesting that the regulation of
protein synthesis of the targets is evolutionar-
ily conserved. For example, the microtubule-
associated protein 1B (MAP1B) is a target of
FMRP in mammals, and its Drosophila ho-
molog futsch is a target of the Drosophila or-
thologue (dfmr1) (Pan et al. 2004). Addi-
tional dfmr1 targets are rac1 and pick pocket
mRNAs, which are involved in synaptic func-
tion and development (Lee et al. 2003, Xu
et al. 2004). Zhang et al. (1995) identified
two autosomal paralogs of FMRP, FXR1P, and
FXR2P. FXR1P and FXR2P contain two KH
domains, an RGG box and nucleus localiza-
tion, and export signal motifs. Both proteins
bind RNA, associate with ribosomes, inter-
act with FMRP (Ceman et al. 1999, Zhang
et al. 1995), and show overlapping expression
patterns (Bakker et al. 2000, Tamanini et al.
1996). Thus investigators predict that mem-
bers of this family of fragile X–related pro-
teins (FXR) might compensate for each other.
Genetic studies are beginning to provide sup-
port from this prediction. Fxr2 null mice,
like Fmr1 mice, display hyperactivity and de-
creased acoustic startle response; however, the
Fmr1/Fxr2 double knockout mice have ex-
aggerated behavioral responses in open field,
acoustic startle responses, prepulse inhibition,
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Metabotrophic
GluR (mGluR):
Postsynaptic G
protein–coupled
receptors for the
excitatory
neurotransmitter
glutamate
and conditioned fear when compared with
either Fmr1 or Fxr2 null mutants (Spencer
et al. 2006). Electrophysiological studies
in the Fmr1 null mice revealed selec-
tive enhancement of metabotropic glutamate
receptor–(mGluR) dependent long-term de-
pression (LTD) (Huber et al. 2002). Knowl-
edge about the functions and localization of
FMRP is providing clues about the mecha-
nism underlying the enhancement of mGluR-
dependent LTD. The recent finding that
mGluR stimulation increases the translation
of FMRP, which in turn suppresses the trans-
lation of other proteins at the synapse, pro-
vided a molecular link between FMRP func-
tion and mGluR-dependent activity (Todd
et al. 2003). Loss of such suppression in Fmr1
null mice led to the proposal that FMRP
suppresses mGluR-stimulated protein syn-
thesis in dendrites and explains why mGluR-
stimulated LTD is enhanced (Figure 1). This
proposal is supported by in vivo data where
mGluR antagonists rescue the behavioral and
neurological deficits of dfmr1 null flies and
Fmr1 null mice (McBride et al. 2005, Yan
et al. 2005). The exact mechanism by which
FMRP plays a role in mGluR-induced LTD
is becoming more complex on the basis
of investigations of protein levels, including
those of FMRP. It is interesting that mGluR-
stimulated protein synthesis requires FMRP
(Todd et al. 2003, Weiler et al. 2004); however,
the increase in FMRP is transient because
FMRP is rapidly degraded by the ubiquitin-
proteasome pathway (Hou et al. 2006).
Degradation of FMRP allows the translation
of FMRP-bound mRNAs, which in turn leads
to internalization of the AMPA receptor and
the mGluR-LTD. In the absence of FMRP in
Fmr1 null mice, there is no increase in pro-
tein synthesis because mRNAs that are nor-
mally kept in check by FMRP are maximally
translated, causing increased AMPA receptor
internalization–enhanced mGluR-LTD (Hou
et al. 2006, Nosyreva & Huber 2006). This
model predicts that either inhibition of the
ubiquitin proteasome system or increased lev-
els of FMRP would decrease mGluR-LTD,
which proved to be true. Consistent with this
prediction, inhibition of the proteasome has
no effect on mGluR-LTD in Fmr1 null mice
(Hou et al. 2006).
Exactly how FMRP inhibits the transla-
tion of the mRNAs it binds is also gradually
being elucidated through the demonstration
that FMRP cooperates with microRNAs
(miRNAs) to suppress translation. MicroR-
NAs are noncoding RNAs that anneal to
partially complementary mRNAs and use the
RNA-induced silencing complex (RISC) to
suppress translation of such target RNAs.
The Argonaute proteins AGO1 and AGO2,
components of RISC, interact with FMRP,
and this interaction is crucial for the function
of dfmr1 and its role in synaptic plasticity
( Jin et al. 2004, Xu et al. 2004). Investigators
have proposed that FMRP and its mRNA
complexes interact with RISC in the cy-
toplasm, to suppress the translation of the
mRNAs (Figure 1). Neuronal stimulation
will increase the transport of mRNAs in
granules to the dendrites and will activate
the proteasome to degrade components of
RISC and dissociation of FMRP, permitting
the local translation of the released mRNAs.
Taken together, the data clearly suggest that
FMRP plays a crucial role in dynamically
regulating mRNA translation at the synapse
and provide insight about the molecular
changes underlying the cognitive deficits and
synaptic changes in fragile X syndrome.
Development of therapeutics. The ad-
vances in understanding the pathogenesis of
various trinucleotide repeat diseases are be-
ginning to reveal potential targets for thera-
peutic intervention. In the case of the frag-
ile X syndrome, the hypermethylation at the
FMR1 promoter along with decreased acety-
lation underlie gene silencing. Although in
vitro treatments of lymphoblasts of fragile X
patients using 5-azadeoxycytidine, an agent
that causes demethylation at CpG sites, in-
crease levels of FMR1 and FMRP, such ther-
apy is not suitable for clinical use owing to
the toxicity of this drug (Chiurazzi et al.
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Nuclear
interacting
protiens
Cytoplasmic
interacting
protiens
Dendritic
spine
Spine
Elongated
spine
FMRP
mRNP
formation
FMRP
miRNA / RISC
RNA
Polyribosome
Presynaptic
terminal
Presynaptic
terminal
Unaffected
Fragile X
NMDA
receptor
mGluR
AMPA
receptor
Protein
synthesis
Figure 1
The function of FMRP and its pathogenic effects on the synapse. FMRP binds RNA molecules and
regulates their translation by controlling their stability and release to the polyribosome. This
translational control is very critical at the synapse, where local protein synthesis is needed during
neuronal activity. Spine morphology is altered in neurons of fragile X patients whereby there is an
increased number of long immature-looking spines. Stimulation of postsynaptic mGluR results in
increased protein synthesis and internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptors, an event critical for long-term depression. FMRP through binding RNAs puts
the break on protein synthesis and dampens this response. In fragile X neurons, protein synthesis,
internalization of AMPA and long-term depression are exaggerated in the absence of FMRP.
1998). Whether approaches using less toxic
demethylating agents with or without HDAC
inhibitor will prove useful remains to be seen.
The finding that mGluR antagonists suppress
abnormalities in the synaptic plasticity ob-
served in Drosophila and mouse models war-
rants further investigation of this drug class as
potential therapeutics.
Fragile XE Syndrome
Clinicopathology. Patients with fragile XE
syndrome (FRAXE) present with mild men-
tal retardation, learning deficits, and devel-
opmental delay (Mulley et al. 1995). Some
FRAXE patients may present with behav-
ioral abnormalities such as attention deficit
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and hyperactivity, but FRAXE patients do
not manifest physical abnormalities and gen-
erally are higher functioning than FRAXA
patients.
Mutation and gene product. FRAXE is
caused by expansion of a CCG repeat in the
5
UTR of the fragile X mental retardation
2(FMR2) gene. When the CCG repeat ex-
pands beyond 200, the CpG island upstream
of the FMR2 gene is hypermethylated causing
transcriptional silencing of FMR2 and loss of
protein function. Consistent with this occur-
rence, FMR2 deletion results in phenotypes
similar to those caused by CCG expansion
(Gecz et al. 1996, Gu et al. 1996, Knight et al.
1993). The FMR2 protein is a nuclear pro-
tein and a member of a family of proline- and
serine-rich proteins believed to be transcrip-
tion factors (Gecz et al. 1997, Nilson et al.
1997).
Pathogenesis studies. The FMR2 RNA is
expressed in peripheral tissues and in the
brain, where it is most abundant in the hip-
pocampus and amygdala (W.J. Miller et al.
2000). Characterization of mice lacking Fmr2
and of Drosophila lacking the ortholog lil-
liputian provided insight about the in vivo
functions of FMR2. Mice lacking Fmr2 have
impaired conditioned fear response and sen-
sory perception as well as abnormal hip-
pocampal synaptic plasticity (Gu et al. 2002).
Loss of function of Lilliputian perturbs em-
bryogenesis because of alterations in a variety
of signaling pathways including transforming
growth factor β (TGFB), mitogen-activated
protein kinase (MAPK), and phosphoinosi-
tide 3 kinase (PI3K) (Su et al. 2001, Wittwer
et al. 2001).
Friedreich Ataxia
Clinicopathology. Friedreich ataxia (FRDA)
is the most common inherited ataxia, oc-
curring in 1 in 50,000 individuals (Cossee
et al. 1997). The disease is typically charac-
terized by ataxia and abnormalities in corti-
cospinal tract function. Friedreich attributed
these symptoms to spinal cord abnormalities
(Friedreich 1863), but further studies revealed
that the medulla, cerebral cortex, and periph-
eral nerves are also involved (De Pablos et al.
1991, Hart et al. 1986). Symptoms of FRDA
typically become apparent by 10 years of age,
although onsets as early as two years or as late
as adulthood have been described. Patients
typically present with progressive gait ataxia,
usually owing to loss of proprioception. Fol-
lowing the ataxia, the upper extremities be-
come uncoordinated, tremors become appar-
ent, and distal muscles begin to waste. Some
choreoform movements may develop, and pa-
tients suffer from dysarthria, nystagmus, as
well as irregular ocular pursuit and dysmetric
saccades. As the disease progresses, cataracts,
optic atrophy, retinitis pigmentosa, and audi-
tory dysfunction may occur in several patients
(Cassandro et al. 1986). Position and vibration
senses are grossly impaired, and deformities
such as club foot and pes cavus are common.
Most FRDA patients develop a cardiomyopa-
thy, and as the disease advances, arrhythmias
and congestive heart failure become more fre-
quent (Child et al. 1986). One third of the pa-
tients develop diabetes or glucose intolerance
(Fantus et al. 1991). FRDA progresses to cause
lethality in most patients by the fourth or fifth
decade. Imaging studies reveal atrophy of up-
per spinal cord and cerebellum (Wessel et al.
1989). Pathological studies reveal atrophy of
the spinal cord, especially the dorsal columns,
spinocerebellar tracts, and coticospinal tracts
(Greenfield 1954). Some degeneration occurs
in the cerebellar cortex with minimal deep nu-
clei involvement. Researchers have reported
subtle neuronal changes affecting Betz cells
of the cerebral cortex. In the heart, myo-
pathic changes represent the most prominent
pathology ( James et al. 1987).
Mutation and gene product. FRDA is an
autosomal recessive disorder caused by the
expansion of an unstable GAA repeat in the
first intron of the FRDA gene (also known
as FXN), which encodes frataxin (Campuzano
582 Orr
·
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    • "Many observations signify mutational causes in multiple related neurodegenerative diseases. These include similar genetic and clinical features [30,36]. In many of the neurodegenerative diseases, the expanded CAG trinucleotide repeats are identified within a coding region. "
    [Show abstract] [Hide abstract] ABSTRACT: Neurodegenerative disorders are commonly encountered in medical practices. Such diseases can lead to major morbidity and mortality among the affected individuals. The molecular pathogenesis of these disorders is not yet clear. Recent literature has revealed that mutations in RNA-binding proteins are a key cause of several human neuronal-based diseases. This review discusses the role of RNA metabolism in neurological diseases with specific emphasis on roles of RNA translation and microRNAs in neurodegeneration, RNA-mediated toxicity, repeat expansion diseases and RNA metabolism, molecular pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia, and neurobiology of survival motor neuron (SMN) and spinal muscular atrophy.
    Full-text · Article · May 2016 · Balkan Journal of Medical Genetics
    • "Spinocerebellar ataxia type 1 (SCA1) is a late-onset, fatal, dominantly inherited neurodegenerative disease caused by the expansion of a trinucleotide CAG repeat in the coding region of the ATXN1 gene that, in turn, produces an abnormally long polyglutamine (polyQ) tract in the ataxin-1 (ATXN1) protein (Banfi et al., 1994; Servadio et al., 1995; Gatchel and Zoghbi, 2005; Lagalwar and Orr, 2013). As such, SCA1 is similar to eight other polyQ diseases, including Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral pallidoluysian atrophy (DRPLA), and the spinocerebellar ataxias types 2, 3, 6, 7, and 17 (Zoghbi and Orr, 2000; Orr and Zoghbi, 2007). SCA1 is characterized by the progressive loss of motor coordination, usually beginning with an impaired gait and balance, and cognitive impairments (Orr et al., 1993; Robitaille et al., 1995; Abele et al., 1997). "
    [Show abstract] [Hide abstract] ABSTRACT: Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in ataxin-1 (ATXN1). The pathological hallmarks of SCA1 are the loss of cerebellar Purkinje cells and neurons in the brainstem and the presence of nuclear aggregates containing the polyQ-expanded ATXN1 protein. Heat shock protein 90 (Hsp90) inhibitors have been shown to reduce polyQ-induced toxicity. This study was designed to examine the therapeutic effects of BIIB021, a purine-scaffold Hsp90 inhibitor, on the protein homeostasis of polyQ-expanded mutant ATXN1 in a cell culture model of SCA1. Our results demonstrated that BIIB021 activated heat shock factor 1 (HSF1) and suppressed the abnormal accumulation of ATXN1 and its toxicity. The pharmacological degradation of mutant ATXN1 via activated HSF1 was dependent on both the proteasome and autophagy systems. These findings indicate that HSF1 is a key molecule in the regulation of the protein homeostasis of the polyQ-expanded mutant ATXN1 and that Hsp90 has potential as a novel therapeutic target in patients with SCA1.
    No preview · Article · Apr 2016 · Neuroscience
  • Source
    • "SBMA is caused by the expansion of a polyglutamine tract in the gene encoding AR [43]. Polyglutamine expansions in specific genes are responsible for eight other neurodegenerative diseases, namely Huntington's disease (HD), dentatorubral–pallidoluysian atrophy , and spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, and 17 [67] . A unique feature of SBMA in the family of polyglutamine diseases is sex specificity: full manifestations are restricted to males. "
    [Show abstract] [Hide abstract] ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1α) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1α, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early-onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients.
    Full-text · Article · Mar 2016 · Acta Neuropathologica
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