DOI: 10.1093/brain/awh278
Brain (2004), 127, 2385–2405
INVITED REVIEW
Trinucleotide repeats and neurodegenerative
disease
C. M. Everett and N. W. Wood
Institute of Neurology, National Hospital for Neurology
and Neurosurgery, London, UK.
Correspondence to: Professor N. W. Wood, Institute of
Neurology, National Hospital for Neurology and
Neurosurgery, Queen Square, London WC1N 3BG, UK.
E-mail: [email protected].
Summary
Major insights have been attained into the molecular pathology of the trinucleotide repeat neurodegenerative diseases
over the past decade. Genetic definition has allowed subclassification into translated polyglutamine diseases, which are
due to CAG repeat expansions, and a more heterogeneous
group in which the trinucleotide repeat remains untranslated. The polyglutamine disorders are due to a toxic gain of
function of mutant expanded proteins. Neuronal intranuclear inclusions (NIIs) characteristically occur. Protein misfolding, interference with DNA transcription and RNA
processing, activation of apoptosis and dysfunction of cytoplasmic elements have all been invoked in the toxic process.
The end result is apoptotic cell death with many aspects of
neuronal function being perturbed. Promising progress has
been made into arresting and reversing neurodegeneration
in both cellular and animal models. The molecular mechanisms underlying the untranslated group remain less clear.
Impedance of gene transcription secondary to abnormal
DNA structures formed by repeats, modification of chromatin gene packaging and dysfunction at the RNA level have all
been suggested as possible pathological mechanisms. These
diseases remain irreversible. It is hoped that clarification of
the molecular pathogenic mechanisms will provide the tools
for future therapeutic intervention.
Keywords: trinucleotide repeat; polyglutamine expansion; neuronal intranuclear inclusion; transcription factors; chromatin
Abbreviations: AR = androgen receptor; BDNF = brain-derived neurotrophic factor; CACNAIA = a1A subunit of a voltagegated calcium channel; cAMP = cyclic AMP; CBP = CREB binding protein; CRE = cAMP response element;
CREB = CRE binding protein; DRPLA = dentatorubralpallidoluysian atrophy; FRDA = Friedreich’s ataxia;
hCD2 = human CD2 reporter gene; HD = Huntington’s disease; HDAC = histone deacetylase; HDAC = histone deacetylase;
hsp = heat shock protein; Htt = human huntingtin; htt = murine huntingtin; ISC = iron–sulphur cluster;
NII = neuronal intranuclear inclusion; polyQ = expanded polyglutamine repeat; SCA = spinocerebellar ataxia;
TBP = TATA binding protein; yfhlp = yeast frataxin homologue 1 protein
Received March 14, 2004. Revised May 11, 2004. Accepted June 10, 2004. Advanced Access publication August 25, 2004
Introduction
The number of neurodegenerative trinucleotide repeat diseases is increasing, as is the complexity of their molecular
pathology. Broadly, they fall into two distinct classes. Firstly
there are the polyglutamine repeat disorders, in which the
expanded repeat is translated into an expanded polyglutamine
(polyQ) tract, which results in formation of protein aggregations within the cell. The presence of the polyQ tract is thought
to result in a toxic gain of function of the mutant protein. The
second class, in which the trinucleotide repeat is present in an
untranslated region of a gene, has more varied molecular
Brain Vol. 127 No. 11
#
mechanisms, including gene repression. Table 1 summarizes
the two classes. This review discusses the molecular mechanisms of neuronal death in these neurodegenerative diseases
rather than providing a detailed description of clinical features.
The polyglutamine repeat diseases
The archetypal polyQ repeat disease is Huntington’s disease,
which will be emphasized as it illustrates many of the
Guarantors of Brain 2004; all rights reserved
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C. M. Everett and N. W. Wood
Table 1 The two classes of trinucleotide repeat diseases
Translated (polyQ)
triplet repeat diseases
Disease
HD
DRPLA
SCA 1, 2, 3, 6, 7, 17
Kennedy’s disease
*Diseases
Untranslated triplet
repeat diseases
Triplet
repeat
sequence
CAG
CAG
CAG
CAG
Disease
SCA 8
SCA 12
FRDA
Myotonic
dystrophy*
Fragile X
syndrome*
Triplet
repeat
sequence
CTG
CAG
GAA
CTG
CGG
in which neurodegeneration is not a feature.
pathogenic principles of the group and is the most common.
Others include the spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7
and 17, dentatorubral pallidoluysian atrophy (DRPLA) and
Kennedy’s disease.
George Huntington described Huntington’s disease (HD) in
1872. The HD locus was localized to chromosome 4p16 in
1983 (Gusella et al., 1983). The genetic defect of an unstable
expanded CAG repeat in the first exon of the huntingtin (Htt)
gene was defined in 1993 (Huntington’s Disease Collaborative Research Group, 1993). Interestingly, a CAG repeat
expansion within an alternatively spliced exon of the junctophilin 3 gene has been found to be responsible for an HD-like
phenotype in African–Americans (Holmes et al., 2001).
Genetic features
All of the polyQ repeat diseases are inherited in an autosomal
dominant fashion except for Kennedy’s disease, which is Xlinked recessive. An expanded CAG repeat within the disease
genes encodes a polyQ repeat in the mutant proteins. The
phenomenon of anticipation, in which subsequent generations
have earlier onset and more severe disease, occurs in the
polyQ diseases and can be explained by enlargement of the
expansion over generations and in this group particularly
occurs with paternal transmission.
The unstable CAG repeat in the Htt gene is translated into a
polyQ stretch near the N-terminus of the protein resulting in
mutant Htt. The length of the repeat dictates the age of onset
and severity of disease features (Andrew et al., 1993). In normal
individuals the gene contains eight to 39 repeats (Huntington’s
Disease Collaborative Research Group, 1993). However, the
presence of 37 or more is found in patients, suggesting that the
disease is not fully penetrant in the overlap range (Rubinsztein
et al., 1996). Age of onset is inversely correlated with length of
the trinucleotide repeat (Trottier et al., 1994; Brandt et al., 1996;
McNeil et al., 1997). Repeats of 40–50 are found in cases with
onset in middle age (90–95% of cases), while over 60 repeats
usually results in juvenile HD. However, CAG repeat length
does not fully explain the differences in age of onset. Other
genes may play a role (Kehoe et al., 1999) and polymorphisms
surrounding the CAG repeat could be important (Vuillaume
et al., 1998).
Dentatorubralpallidoluysian atrophy (DRPLA) is caused
by an expanded CAG repeat in the 50 coding region of the
atrophin-1 gene, located on the short arm of chromosome 12
(Koide et al., 1994; Nagafuchi et al., 1994). The disease is
most common in Japan. Age of onset is tightly correlated to
repeat length, with different clinical syndromes manifest at
differing ages of onset. There is a degree of overlap in the
manifestations of DRPLA and HD. The length of the repeat on
the normal allele is 7–34 and on the expanded 58–88 (Ikeuchi
et al., 1995; Komure et al., 1995).
There are at least 25 different SCAs. The causal mutation in
eight is expansion of a trinucleotide repeat. SCA 1, 2, 3, 6, 7
and 17 are due to a translated CAG expansion whereas SCA8
and 12 are suggested to be due to an untranslated CTG and
CAG expansion respectively (Table 2). Prior to the genetic
definition of these disorders, they were classified as autosomal
dominant cerebellar ataxias according to clinical criteria
(Harding, 1982) (Table 3). The SCA genes encode a group
of proteins known as the ataxins. Ataxins 1, 2, 3 and 7 are
expressed ubiquitously in nervous and other tissues. The normal cellular function of the ataxins is unknown. TATA binding protein (TBP) is a ubiquitous transcription factor and
harbours the polyQ expansion in SCA 17. The polyQ tracts
are near the N-terminus in TBP and ataxins 1, 2, 7 and near the
C-terminus in ataxin-3. In the presence of an expanded polyQ
tract the ataxins and TBP form ubiquitinated NIIs. SCA 6 is
less closely related to the other polyQ SCAs. The expanded
CAG repeat occurs at the 30 end of the CACNA1A gene
encoding the a1A subunit of the P/Q-type voltage gated calcium channel (Zhuchenko et al., 1997). SCA 6 has the shortest
CAG repeat responsible for disease and is much more stable
both mitotically and meiotically than the CAG repeats found
in other SCAs.
Also known as X-linked recessive spinal and bulbar
muscular atrophy, Kennedy’s disease is due to the pathological expansion of a CAG repeat in exon 1 of the androgen
receptor (AR) gene located on the long arm of the X chromosome. It was the first trinucleotide repeat disease described
(La Spada et al., 1991). Kennedy’s disease is primarily a disorder of motor neurons with degeneration in the spinal cord
and brainstem (Sobue et al., 1989). Onset is usually from
the second to fourth decade with slow progression and
long survival. The normal range of the CAG repeat is
11–33, patients having between 38 and 62 (Fischbeck et al.,
1999). The length of CAG repeats correlates well with the age
of onset of disease (Igarashi et al., 1992). Anticipation
occurs albeit less commonly than in other polyQ diseases,
reflecting the greater stability of the CAG repeat (Watanabe
et al., 1996).
Molecular mechanisms
The molecular processes involved in polyQ toxicity are
broadly summarized in Fig. 1.
Trinucleotide repeats and neurodegeneration
2387
Table 2 Summary of genetic features of the trinucleotide repeat spinocerebellar ataxias
Disorder
Gene
locus
References
Gene
product
Trinucleotide
repeat
SCA 1
SCA 2
6p23
12q24.1
Yakura et al., 1974
Gispert et al., 1993
Ataxin-1
Ataxin-2
CAG
CAG
SCA 3
14q32.1
Ataxin-3
SCA 6
SCA 7
19p13
3p14–21.1
SCA 8
SCA 12
SCA 17
13q21
5q31–33
6p27
Takiyama et al., 1993;
Kawaguchi et al., 1994
Zhuchenko et al., 1997
Benomar et al., 1995;
Gouw et al., 1995
Koob et al., 1999
Holmes et al., 1999
Normal
range
Pathological
range
6–44
14–31
39–83
33–64
CAG
Orr et al., 1993
Imbert et al., 1996;
Pulst et al., 1996;
Sanpei et al., 1996
Kawaguchi et al., 1994
12–40
54–86
CACNA1A
Ataxin-7
CAG
CAG
Zhuchenko et al., 1997
David et al., 1997
4–20
4–27
–
PPP2R2B
TBP
CTG
CAG
CAG
Koob et al., 1999
Holmes et al., 1999
Nakamura et al., 2001
15–91
<29
25–42
20–31
37 to >200
100–155
66–93
45 and 63
PPP2R2B = protein phosphatase 2 regulatory subunit B.
Table 3 Harding’s classification of the autosomal dominant cerebellar ataxias
ADCA I
ADCA II
ADCA III
Cerebellar syndrome with involvement of other regions
within the CNS, i.e. pyramidal and extrapyramidal signs,
supranuclear ophthalmoplegia and dementia
SCA 1, 2, 3, 4*, 8, 12, 17, 25*
Cerebellar syndrome with
pigmentary retinal degeneration
Pure cerebellar syndrome
SCA 7
SCA 5*, 6, 10, 11*, 14, 15*, 22*
*Genetic
mutation as yet unidentified. ADCA = autosomal dominant cerebellar ataxia.
The proteins
The molecular mechanisms involved in polyQ neurodegeneration are complex. The cellular roles of the wild-type and
mutant proteins are becoming clearer, although they remain
far from fully defined.
The Htt gene has 67 exons, with the CAG repeat in the first.
Htt is a protein of 3140 amino acids with a molecular mass of
349 kDa (Huntington’s Disease Collaborative Research
Group, 1993). It has no major homology to any other
known protein, although it contains a motif involved in cytoplasmic transport (Andrade and Bork, 1995). Htt is ubiquitously expressed (Strong et al., 1993; Trottier et al., 1995). In
the brain it is found predominantly in neurons with little
expression in glial cells (Li et al., 1995; Sharp et al.,
1995). During development it appears in the mammalian
brain by gestation day 15 (Bhide et al., 1996). The precise
localization of wild-type Htt within cells is still not certain.
Most studies suggest that it is predominantly located in the
cytoplasm (Aronin et al., 1995; DiFiglia et al., 1995; Sharp
et al., 1995; Ferrante et al., 1997; Sapp et al., 1997; Jones,
1999) but there is evidence of localization to the nucleus (De
Rooij et al., 1996). Htt may shuttle between the nuclear and
cytoplasmic compartments (Ross et al., 1999).
Htt is highly conserved through evolution, suggesting an
important role (Sharp and Ross, 1996). In knockout mice in
which the homologous murine (Hdh) gene is inactivated,
nullizygous embryos die at 8–10 days of gestation, indicating
the essential role for Htt in development (Duyao et al., 1995;
Nasir et al., 1995; Zeitlin et al., 1995).
Fig. 1 Summary of molecular mechanisms involved in the
pathogenesis of polyglutamine diseases using HD as an example.
Broad processes involved in mutant Htt toxicity. These processes
may be shared in all the polyQ repeat diseases. Mutant polyQ Htt
gains several toxic functions within the cell. Loss of function of
polyQ proteins may also be relevant but this may be a lesser effect
compared with toxic gain of function. The toxic effects are not
mutually exclusive. For example, NIIs sequester transcription
factors, resulting in impaired gene expression. In addition, mutant
polyQ Htt may also have more direct effects on gene expression
by binding to transcription factors directly. NII formation,
interference with cytoskeletal and vesicular functions and effects
on gene expression may all result in apoptosis. The presence of
mutant polyQ Htt may also directly cause apoptosis.
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C. M. Everett and N. W. Wood
Htt associates with clathrin-coated vesicles, microtubules
and cytoplasmic granules and may have a role in intracellular
transport (DiFiglia et al., 1995; Gutekunst et al., 1995; Sapp
et al., 1997). In studies of axonal transport, Htt was anteroand retrogradely transported (Block-Galarza et al., 1997),
giving further credence to a role in vesicle function. Indeed,
mutant Htt containing an expanded polyglutamine tract inhibits fast axonal transport (Szebenyi et al., 2003).
It is thought that mutant Htt harbouring the expanded polyQ
expansion has a toxic gain of function. mRNA from both the
normal and expanded allele are found in HD lymphoblasts and
brain (Ambrose et al., 1994) and mutant Htt mRNA is present
in patients homozygous for the CAG expansion (Huntington’s
Disease Collaborative Research Group, 1993), ruling out a
loss of gene transcription as the cause of the disease. The
occurrence of homozygous HD patients suggests that mutant
Htt maintains its normal function in addition to its toxic
effects. Homozygous knockin mice with 50 CAG repeats
in the homologous murine Hdh gene develop normally,
implying that mutant htt retains the developmental function
of wild-type htt (White et al., 1997). A complicating factor
has emerged in that the postembryonic inactivation of the
murine Hdh gene causes a progressive neurological phenotype with accompanying neurodegeneration (Dragatsis et al.,
2000). Therefore, a subtle loss of function may act concomitantly with the toxic gain of function of mutant Htt in mice. It is
possible that this proposed loss of function and the more clear
toxic gain of function may have adverse effects at different
molecular levels. Indeed, a similar mechanism may occur in
Kennedy’s disease as expression of the mutant AR gene is
reduced in transient transfection assays in a CAG lengthdependent fashion (Choong et al., 1996). This may account
for the lower level of target gene activation that occurs in the
presence of the mutant expanded AR (Mhatre et al., 1993).
The implication is that a loss of function of the AR is also
relevant to pathogenesis. Interestingly, there are examples of
homozygous cases of HD, SCA 3 and SCA 17 (Lang et al.,
1994; Squitieri et al., 2003; Toyoshima et al., 2004), all of
which have a more severe phenotype than found in the usual
heterozygotes. The molecular correlate may be that the double
dose of mutant polyQ protein is more toxic to the cell, in
keeping with the toxic gain of function hypothesis. Also possible, however, is that the low-level loss of function of the
mutant protein, which may be relatively insignificant in the
face of polyQ toxicity, becomes more significant when all of
the protein is mutant. It is also possible that the polyQ load
within cells is crucial. In a Hdh knockin mouse, a CAG
expansion of approximately 72 repeats expanded preferentially in striatal cells with age. Therefore, the increased levels
of polyQ in these cells may account for the selective
degeneration of striatal neurons with time (Kennedy and
Shelbourne, 2000). Dramatic increases in CAG repeat length
in the striatum may occur early on in the disease course
(Kennedy et al., 2003).
The difficulties in elucidating the function of the ataxins
begin with defining their precise cellular localization. Nuclear
and cytoplasmic locales have been suggested, with the possibility of shuttling between compartments. Ataxin-1 is localized predominantly in the nucleus in neuronal tissue and in the
cytoplasm in the periphery. In neuronal tissue it is expressed
at high levels in regions that are affected in SCA 1 (cerebellar
Purkinje cells) and in areas that are not (hippocampus)
(Servadio et al., 1995). The nuclear presence of mutant
ataxin-1 is essential for disease, as transgenic mice do not
develop it if the nuclear localization sequence of ataxin-1 is
disabled (Klement et al., 1998). Ataxin-1 is not dispensable as
knockout mice have learning defects and deficits in hippocampal function (Matilla et al., 1998). Homozygous polyQ
mutant ataxin-1 knockin mice had a phenotype of impaired
memory with no pathological changes (Lorenzetti et al.,
2000). Therefore, prolonged exposure to mutant ataxin-1 at
endogenous levels is probably needed to produce a neurological phenotype. Pathogenesis is likely to be a function of
polyQ length, expressed protein levels and duration of neuronal exposure to the mutant protein.
Wild-type ataxin-2 is located in the cytoplasm and within
the brain is expressed in cerebellar Purkinje cells and other
brainstem nuclei (Huynh et al., 1999). Ataxin-3 is ubiquitously expressed and is present in the cytoplasm in normal and
diseased brain and in transfected cells (Nishiyama et al., 1996;
Paulson et al., 1997a; Schmidt et al., 1998). In contrast, in
neuroblastoma cell lines wild-type ataxin-3 was found predominantly in the nucleus, associating with the inner nuclear
matrix. A putative nuclear localization sequence was proposed and transport into the nucleus occurred independently
of an expanded polyglutamine tract (Tait et al., 1998). Wildtype ataxin-3 may therefore shuttle between the nucleus and
cytoplasm.
Ataxin-7 distributes to the nucleus and associates with the
nuclear matrix and nucleolus in transfected cells. A nuclear
localization sequence has been identified (Kaytor et al., 1999).
Wild-type ataxin-7 colocalizes with an ATPase component of
the 26S proteosome within discrete nuclear foci and high
levels of ataxin-7 are found in cerebellar Purkinje cell nuclei (Matilla et al., 2001). In transgenic mice mutant ataxin-7
N-terminal fragments translocate from the cytoplasm and
accumulate in the nucleus in an age-dependent manner
(Yvert et al., 2001).
Atrophin-1 is ubiquitously expressed and predominantly
cytoplasmic. There is predominantly neuronal expression in
the brain, which is highest in the cerebellum, hippocampus,
substantia nigra and pontine nuclei (Yazawa et al., 1995).
Atrophin-1 mRNA levels are similar in normal and
DRPLA brain (Nishiyama et al., 1997), consistent with the
gain-of-function hypothesis. Atrophin also acts as a transcriptional corepressor in Drosophila (Zhang et al., 2002) and may
therefore be involved in regulating gene expression.
NIIs
Neuronal intranuclear inclusions (NIIs) characteristically
occur in polyQ repeat disease. In vitro, N-terminal mutant
Trinucleotide repeats and neurodegeneration
Htt forms aggregates in a b-pleated sheet conformation similar to amyloid, with a fibrillar structure on electron microscopy, and no such aggregation occurs when a normal polyQ
stretch is present (Scherzinger et al., 1997). PolyQ tracts
above a certain length threshold are thought to form a
‘polar zipper’ and to associate via formation of hydrogen
bonds (Perutz et al., 1994). Htt is a substrate for transglutaminase in vitro with the rate of reaction and polymer formation increasing with polyQ number (Kahlem et al., 1998). It
has been possible to prevent mutant Htt aggregation in vitro
using specific monoclonal antibodies to the polyQ repeat and
a variety of chemical compounds (Heiser et al., 2000). Additionally, a transglutaminase inhibitor used in mutant Nterminal Htt transgenic mice, extended survival and reduced
the appearance of some movement disorders (Karpuj et al.,
2002). Conversely, NII levels were increased in HD transgenic mice with transglutaminase 2 (the major brain transglutaminase) deleted, although both generalized and brain weight
loss were reduced with prolonged survival of the mice (Mastroberardino et al., 2002). Therefore, the role of transglutaminase in aggregate formation remains unclear, although it
may play a role in regulating cell death in HD.
In a neuronal cell culture model, transfection of expanded
mutant cDNA Htt resulted in the formation of NIIs in a polyQ
length- and time-dependent manner. The longer the repeat the
greater the number of NIIs (Kim et al., 1999). Other workers
have found this phenomenon in various cellular models
(Cooper et al., 1998; Li and Li, 1998; Lunkes and Mandel,
1998; Lunkes et al., 1999). The formation of NIIs and toxicity
in rat striatal neurons when an expanded polyQ tract was
linked to an otherwise inert protein demonstrated that the
polyQ stretch was the toxic moiety (Moulder et al., 1999).
Cellular transfection studies have repeatedly shown that
truncated portions of mutant Htt translocate to the nucleus,
are more likely to aggregate and are more toxic than the fulllength protein (Cooper et al., 1998; Hackam et al., 1998;
Lunkes and Mandel, 1998; Martindale et al., 1998; Li
et al., 2000). Indeed, introducing aggregated polyQ peptides
directly into mammalinn nuclei is toxic (Yang et al., 2002). In
some studies, blocking nuclear accumulation of mutant Htt
resulted in less toxicity (Saudou et al., 1998). Addition of a
nuclear export signal to mutant Htt reduced toxicity while
increasing nuclear localization resulted in increased toxicity
(Peters et al., 1999). Others have shown that both nucleus and
cytoplasm are sites for toxic effects (Hackam et al., 1999). In
the Hdh knock-in mouse mutant Htt is translocated into the
nucleus with subsequent formation of N-terminal aggregations, (Wheeler et al., 2000). The mechanism for translocation
of mutant human Htt to the nucleus is uncertain although there
may be a nuclear localization sequence at the N-terminus
(Hackam et al., 1998).
In transgenic mice, truncated N-terminal fragments rather
than full-length mutant Htt may be more toxic but direct
comparison of different transgenic models is difficult, due
to varying construction of transgenes, mouse strains and
expression levels. Generally, however, transgenic mice
with shorter N-terminal constructs have resulted in more
marked phenotypes, with neuronal aggregations forming
and cellular toxicity occurring earlier than in those with
full-length Htt. There is more widespread formation of aggregations in N-terminal mutant Htt transgenic mice, whereas in
a Hdh knockin mouse changes occurred more specifically in
the striatum. It may be that the provision of ready-processed
N-terminal fragments aids toxicity. Full-length mutant Htt,
whether it is derived from a transgene or the endogenous
murine Hdh gene, seems to require long repeats to result in
toxicity. Importantly, however, whatever genetic manipulation is used to generate a murine HD model, N-terminal fragments of mutant Htt are always found within the aggregations
(Mangiarini et al., 1996; Davies et al., 1997; White et al.,
1997; Reddy et al., 1998, 1999; Hodgson et al., 1999; Schilling et al., 1999a; Shelbourne et al., 1999; Li et al., 2000;
Wheeler et al., 2000; Yamamoto et al., 2000; Lin et al., 2001).
Further, co-expression of mutant N-terminal Htt accelerates
the disease process initiated by full-length mutant Htt
(Wheeler et al., 2002).
Table 4 Molecular mechanisms in DRPLA
Process
Details
Ubiquitinated NIIs
Located near neuronal nucleoli (Becher et al., 1998;
Hayashi et al., 1998; Igarashi et al., 1998; Yazawa et al., 1999)
Mutant atrophin-1 found in intranuclear inclusion bodies (Igarashi
et al., 1998)
Five atrophin interacting proteins identified (Wood et al., 1998)
Atrophin interacting protein-2, -4 and -5 all contain ubiquitin ligase
domains. Atrophin-1, like Htt, interacts with glyceraldehyde-3phosphate dehydrogenase (Burke
et al., 1996)
TAFII130, TBP and CREB localize to NIIs (Shimohata et al., 2000)
Transgenic mice made with full-length atrophin-1 containing 65 CAG
repeats developed a marked phenotype of ataxia, seizures, involuntary
movements, weight loss and premature death. Full-length atrophin-1
found in the cytoplasm with truncated forms in the nucleus, both
diffusely and as part of NIIs (Schilling et al., 1999b)
Protein interactions with atrophin-1
Transgenic mice
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C. M. Everett and N. W. Wood
Table 5 Molecular mechanisms in Kennedy’s disease
Process
Details
Ubiquitinated NIIs
Present in motor neurons but also in tissues uninvolved in the disease.
Within neuronal tissues NIIs only present in regions affected by the
disease. Proteolytically cleaved AR found in inclusions (Li et al., 1998a, b)
Cytoplasm important for AR aggregation. Removal of nuclear
localization signals of both wild-type and expanded AR resulted in
massive cytoplasmic aggregation. Rapid targeting to the nucleus
abrogated aggregation (Butler et al., 1998; Becker et al., 2000)
Caspase-3 cleaves the AR in polyQ length-dependent manner. Cleavage
crucial for apoptotic cytotoxicity (Kobayashi et al., 1998; Ellerby et al.,
1999). Phosphorylation of AR via MAP kinase pathway may enhance
cleavage of mutant AR to toxic product (LaFevre-Bernt and
Ellerby, 2003)
Aggregates contain molecular chaperones (Stenoien et al., 1999; Abel
et al., 2001). Overexpression of chaperones reduced aggregation and
toxicity (Stenoien et al., 1999; Kobayashi et al., 2000). Ubiquitin and
proteosome pathways act additively to modulate neurodegeneration in
Drosophila. The SUMO-1 (small ubiquitin-like modifier 1) pathway is
also involved in modulating polyQ toxicity (Chan et al., 2002)
CBP present in NIIs in transgenic mice (Abel et al., 2001).
Overexpression of CBP overcame toxicity (McCampbell et al., 2000)
Present in NIIs implying an attempt to process mutant protein (Stenoien
et al., 1999; Abel et al., 2001)
Large number of CAG repeats (112) are required within a truncated
N-terminal fragment of the AR to generate a neurological phenotype with
associated formation of NIIs (Fischbeck et al., 1999; Abel et al., 2001).
Full-length AR with 120 CAG repeats develop syndrome similar to
Kennedy’s in humans (McManamny et al., 2002)
Cytoplasmic aggregation of AR
Apoptosis
Molecular chaperones
Sequestration of nuclear proteins
The proteosome
Transgenic mice
Similarly, ubiquitinated NIIs occur in DRPLA (Table 4),
Kennedy’s disease (Table 5) and the polyQ SCAs. Ataxin-1
aggregates are found in regions of SCA 1 brain that specifically degenerate and are found in cell lines overexpressing
mutant ataxin-1 (Skinner et al., 1997). In transgenic mice
overexpressing a mutant SCA 1 allele with expression targeted to cerebellar Purkinje cells, a phenotype of progressive
ataxia developed with formation of NIIs (Clark and Orr,
2000). Similar transgenic mice, without the self-association
domain found in ataxin-1, developed a similar phenotype and
Purkinje cell pathology but without NIIs (Klement et al.,
1998), suggesting that NIIs are not the primary pathology.
NIIs of ubiquitinated mutant ataxin-3 aggregations occur in
SCA 3 neurons (Paulson et al., 1997a, b). Mutant ataxin-3
binds to the nuclear matrix, resulting in a conformational
change and exposure of the polyQ tract (Perez et al.,
1999). Exposure of an expanded polyQ may therefore result
in more marked aggregation and binding of other polyQcontaining nuclear proteins. Overexpression of both fulllength and truncated mutant ataxin-3 fragments in cell
lines, transgenic mice and Drosophila resulted in cellular
toxicity, apoptosis and death with the associated formation
of NIIs (Ikeda et al., 1996; Paulson et al., 1997b; Warrick
et al., 1998; Evert et al., 1999). The correlation between NII
formation and cell death was poor, suggesting that NIIs are not
the primary toxic insult. Indeed, in SCA 7 knockin mice
neuronal dysfunction occurred several weeks before NII
formation (Yoo et al., 2003).
Ubiquitinated NIIs have been reported in SCA 2 and SCA 7,
brains although the exact distribution and relationship to
disease remains unclear. SCA 7 NIIs are ubiquitinated in
areas such as the inferior olive, which is severely degenerated
in this disease, but also in the cerebral cortex, which is unaffected (Holmberg et al., 1998; Yvert et al., 2001), an observation that is borne out in transgenic mice (Yvert et al., 2001). In
SCA 17, ubiquitin- and TBP-positive NIIs were found in the
putamen and frontal cortex (Nakamura et al., 2001).
The ubiquitination of NIIs suggests that the ubiquitinproteosome proteolytic pathway of the cell attempts to
clear aggregates. Consistent with this, the 20S proteosome
relocates to aggregates in SCA 1 (Cummings et al., 1998)
and SCA 3 (Chai et al., 1999b). Transgenic mice that express
mutant ataxin-1 but not a ubiquitin-protein ligase have
significantly fewer NIIs but the Purkinje cell pathology is
markedly worse. Thus, preventing ubiquitination of mutant
ataxin-1 results in increased toxicity to the cell, and ubiquitination of mutant ataxin may play an important detoxifying
role (Cummings et al., 1999). The ubiquitin–proteosome
pathway is also important in the metabolism of ataxin-3
aggregations and inhibition of the proteosome complex results
in accumulation of aggregates in a repeat-dependent manner
(Chai et al., 1999b). Proteosome subunits also colocalize with
mutant ataxin-7 NIIs in SCA 7 transgenic mice (Yvert et al.,
2001), transfected cells and brain (Zander et al., 2001). A
specific proteosome subunit is depleted in regions of
the brain affected by neurodegeneration in SCA 7 (Matilla
Trinucleotide repeats and neurodegeneration
et al., 2001) and may account for impaired proteolysis of NIIs.
Interestingly, downregulation of mutant ataxin-7 expression
after early development in transgenic mice did not prevent
progression of retinopathy, suggesting that the toxic effect
may be irreversible (Helmlinger et al., 2004).
NIIs form in SCA 6 Purkinje cell cytoplasm and are not
ubiquitinated. There is, however, marked degeneration of
cerebellar Purkinje cells in SCA 6 and transfection of cells
with mutant CACNA1A resulted in the formation of perinuclear aggregates and apoptotic cell death (Ishikawa et al.,
1999). The presence of an expanded polyQ tract results in
altered function of the calcium channel, which may be responsible for neurodegeneration (Toru et al., 2000). Two other
disorders are caused by mutations in the CACNA1A gene
(Ophoff et al., 1996). Familial hemiplegic migraine is generally caused by missense mutations and episodic ataxia type
2 by nonsense mutations. There is a definite clinical overlap
between these disorders (Denier et al., 1999; Jen et al., 1998;
Yue et al., 1997).
2391
A conditional model of HD has been developed based on
mice expressing an N-terminal mutant Htt fragment with a
CAG expansion of 94 repeats. Reducing expression of the
mutant Htt in symptomatic mice led to a disappearance of NIIs
and an amelioration of the behavioural phenotype. This does
not clarify whether toxicity is caused by NIIs but, importantly,
shows that reduction of mutant Htt expression reverses the
pathological changes and phenotype (Yamamoto et al., 2000).
Recently, interference with polyQ aggregation in HD transgenic mice with disaccharide molecules ameliorated the HD
phenotype (Tanaka et al., 2004). Polypeptides have been
identified that bind to mutant Drosophila huntingtin and interfere with aggregation in a Drosophila model for HD, with a
reduction in lethality (Apostol et al., 2003). Thus, interfering
with mutant htt aggregate formation may have therapeutic
potential (Bates, 2003). Interestingly, there have been suggestions that eliminating mutant Htt in mice may result in sensitization to the remaining mutant htt with hastening of the
disease (Auerbach et al., 2001), which may be relevant to
strategies aimed at reducing mutant Htt in humans.
Neuronal aggregates and their role in
neurodegeneration
Molecular chaperones and NII
Much has been made of the formation of neuronal aggregates
in polyQ neurodegeneration. It is not certain that the aggregates are of primary pathogenic importance in the polyQ repeat
diseases, as suggested above in relation to the SCAs. They may
merely represent end products of an upstream toxic event.
Some have suggested that inclusions serve a protective role
(Saudou et al., 1998).
Aggregate formation does not necessarily result in cell
death. For example, they have been seen in the dentate nucleus
of HD cerebellum, a region of the brain unaffected by
neurodegeneration in HD (Becher et al., 1998). Cellular models show the discrepancy between NII formation and cell
death. In rat primary striatal neurons, NII formation is not
a prerequisite for cell death but mutant Htt must be present in
the nucleus to cause apoptosis (Saudou et al., 1998). Apoptosis in neuroblastoma cell lines was increased in the presence
of mutant Htt but the correlation with NII formation was not
tight (Lunkes and Mandel, 1998; Lunkes et al., 1999).
There is also evidence in transgenic mice for NII formation
without cell death and vice versa. The first transgenic mouse
modelling HD had a phenotype reminiscent of HD, extensive
striatal NIIs but minimal cell death (Mangiarini et al., 1996).
Other mice have striatal loss with minimal or absent NIIs
(Reddy et al., 1998; Aronin et al., 1999; Hodgson et al.,
1999). Interestingly, when a 146 CAG repeat was introduced
into a hypoxanthine phosphoribosyltransferase transgene
(Ordway et al., 1997), abundant NIIs developed throughout
the brain and the animals developed a late onset neurological
phenotype with multiple seizures and early death. These mice
demonstrate that polyQ incorporation into a cytoplasmic protein (hypoxanthine phosphoribosyltransferase) renders it
toxic, causing translocation into the nucleus with subsequent
formation of NIIs and neuronal dysfunction.
Abnormal folding of polyQ-containing proteins with impaired
protein processing has been invoked as a mechanism of aggregation and inclusion formation. A class of proteins known as
molecular chaperones is involved in this process. Examples
are heat shock protein (Hsp) 70 and Hsc70. A co-chaperone
class known as Hsp40, with members human DNAJ1 (Hdj1)
and Hdj2, facilitates Hsp70 action. Hsp40 and Hsp70 are both
involved in the clearance of misfolded proteins via the ubiquitin-proteosome pathway (Bercovich et al., 1997). Hdj2 and
Hsc70 were associated with nuclear aggregates in HD cell
culture and transgenic mice models and overexpression of
Hdj1 and Hsc70 reduced aggregate formation. Hsp70 levels
were upregulated in both the cellular model and in transgenic
mice (Jana et al., 2000). Therefore, mutant Htt may elicit a
stress response causing molecular chaperone expression, perhaps in an attempt to clear aggregates. On the other hand,
sequestration of protein chaperones into aggregates may result
in misfolding and reduced clearance of other crucial cellular
proteins. Whether chaperones are directly involved in aggregation itself is not clear. Notably, a recent study in a Drosophila
model of HD found the presence of suppressor genes capable of
modifying the phenotype with one of the predicted proteins
being Drosophila Hdj-1 (Kazemi-Esfarjani and Benzer, 2000).
Overexpression of protein chaperones in mutant ataxin1-transfected HeLA cells reduced aggregate formation
(Cummings et al., 1998), consistent with the hypothesis of
protein misfolding leading to aggregate formation in
polyQ diseases. Hdj-2 is associated with NIIs in SCA 1 (Cummings et al., 1998), SCA 3 (Chai et al., 1999a, b) and in SCA7
transgenic mice (Yvert et al., 2001), transfected cells and SCA
7 brain (Zander et al., 2001). Overexpression of Hsp70 in
SCA 1 transgenic mice also suppressed neurodegeneration
and improved motor function (Cummings et al., 2001).
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C. M. Everett and N. W. Wood
Additionally, in a SCA3 Drosophila model the molecular
chaperone Hsp70 was colocalized with NIIs and its overexpression ameliorated neurodegeneration (Warrick et al., 1999).
Hsp40 also ameliorated toxicity in a SCA 3 Drosophila
model (Chan et al., 2000). Further, these proteins are also
contained within aggregates in Kennedy’s disease (Table 5).
This provides further evidence for a protein-misfolding model
for polyQ toxicity.
Apoptosis in polyglutamine diseases
It is becoming increasingly apparent that apoptosis is crucial
to neurodegeneration in polyQ repeat diseases. Cellular
models of HD have shown that toxicity is mediated by
increased sensitivity to apoptotic stress (Saudou et al.,
1998; Kim et al., 1999). Both wild-type and mutant Htt are
cleaved at sites within the N-terminal by the pro-apoptotic
caspases (Goldberg et al., 1996; Wellington et al., 1998).
Therefore, the apoptotic pathway may be self-perpetuating,
with the cleavage of mutant huntingtin activating apoptosis
(and caspases) and hence generating more toxic N-terminal
fragments. Wild-type Htt itself has been proposed to protect
cells from apoptotic signals. (Rigamonti et al., 2000). Preventing cleavage of mutant Htt resulted in reduced aggregate
formation and reduced toxicity in apoptotically stressed cells
(Wellington et al., 2000). Inhibiting caspases can abrogate the
formation of NII and prolong the survival of cells (Kim et al.,
1999; Moulder et al., 1999; Wang et al., 1999; Wellington
et al., 2000), although different inhibitors have different
effects (Kim et al., 1999). Interestingly, a caspase-1-deficient
mouse used in a neurotoxic model of HD protected against
neurotoxicity, implicating apoptosis in neurodegeneration
(Andreassen et al., 2000). It has been demonstrated that caspase activation occurs in HD brain and lymphoblasts (Sanchez
et al., 1999; Sawa et al., 1999). Lately, activated dsRNAdependent protein kinase has been found at high levels in
areas of the brain specifically affected in HD (Peel et al.,
2001). dsRNA-dependent protein kinase has been implicated
in the stress response, triggering apoptosis. Atrophin-1 is also
cleaved by caspase, resulting in nuclear translocation and
toxicity (Nucifora et al., 2003).
Promising inroads have been made into slowing HD disease
progression by interfering with apoptotic processes. Inhibiting
caspase-1 in transgenic mice expressing mutant Htt has
delayed the appearance of NIIs, neurotransmitter alterations
and the onset of symptoms (Ona et al., 1999). HD-transgenic
mice treated with minocycline, which is known to downregulate caspase expression in other disease models, delays
the onset of symptoms and prevents the upregulation of
caspase-1 and -3 expression (Chen et al., 2000).
Interactions of polyglutamine containing
proteins with other cellular proteins
The polyQ proteins interact with other cellular proteins
and mutant Htt, atrophin-1, ataxins and AR have several
interactions in common (Tables 4–7). Wild-type Htt is
known to associate with several predominantly cytoplasmic
proteins (Table 6), giving clues to its usual cellular functions.
These interactions may all be perturbed in HD. Indeed, Httassociated protein-1, glyceraldehyde-3-phosphate dehydrogenase and calmodulin show enhanced binding to mutant
Htt, which may result in toxicity. A Hdh expanded PolyQ
knockin mouse showed progressive formation of nuclear
aggregates in the striatum and formation of presynaptic inclusions with synaptic vesicles. Given that N-terminal mutant Htt
bound to synaptic vesicles in a CAG length-dependent manner
and impaired glutamate uptake in vitro, binding of mutant Htt
to vesicles in vivo may play a role in toxicity (Li et al., 2000).
Aggregation of mutant polyQ proteins results in the recruitment of other polyQ-containing proteins. Therefore, sequestration of endogenous proteins containing polyQ tracts may
occur (Preisinger et al., 1999). Several transcription factors
contain short polyQ repeats (see below). Altering the balance
of transcription factors within the nucleus may have profound
effects on gene expression with potentially toxic effects. A
variety of transcription factors have been found to colocalize
with NIIs and several interact directly with the mutant proteins (Tables 4–7 and below).
Mutant polyglutamine proteins and gene
expression
A common transcriptional activator cyclic AMP (cAMP)
response element (CRE) binding protein (CREB), along
with its coactivator CREB binding protein (CBP), has been
strongly implicated in mutant Htt-induced gene repression
(Fig. 2). Mutant Htt causes repression of CBP-regulated
gene expression, which can be overcome in cell culture by
overexpressing CBP (Nucifora et al., 2001). Mutant Htt may
also promote CBP degradation (Jiang et al., 2003). TAFII130
is a coactivator for CREB-regulated transcriptional activation.
TAFII130 binds directly to polyQ stretches with the consequence of impaired CREB-dependent transcriptional activation, which again can be rescued by overexpression of
TAFII130 (Shimohata et al., 2000). Mice with the Creb
gene disrupted postnatally developed neurodegeneration
in the hippocampus and striatum (Mantamadiotis et al.,
2002). Suggestions have been made that transcription from
genes regulated by the cAMP response element may be
impaired in HD due to reduced cAMP levels secondary to
impaired energy metabolism in the cell (Gines et al., 2003).
CREB/CBP recruitment to NIIs or the interaction with mutant
polyQ proteins also occurs in DRPLA, SCA 3, SCA 7 and
Kennedy’s disease (Tables 4–7). Thus, disruption of CREB/
CBP-mediated gene expression may be a common mechanism
of neurodegeneration in polyQ repeat diseases.
CREB-binding protein and p300/CBP-associated factor
have intrinsic histone acetyl transferase activity. Acetylation
of DNA histones is generally associated with transcriptional
activation. PolyQ Htt binds to CBP and p300/CBP-associated
Trinucleotide repeats and neurodegeneration
2393
Table 6 Protein interactions with huntingtin
Protein
References
Cellular role
Htt associated protein 1
Htt interacting protein 1
Li et al., 1995
Kalchman et al., 1997;
Wanker et al., 1997;
Singaraja et al., 2002
Goldberg et al., 1996
Kalchman et al., 1996
Burke et al., 1996
Cytoskeletal, microtubule and vesicle function
Cytoskeletal, microtubule and vesicle function
Boutell et al., 1998;
Jones, 1999
Faber et al., 1998; Gusella
and MacDonald, 1998
Bao et al., 1996
Faber et al., 1998;
Passani et al., 2000
Amino acid metabolism
Caspase-3
Htt interacting protein 2
Glyceraldehyde-3-phosphate
dehydrogenase
Cystathionine b synthase
a-Adaptin
Calmodulin
Htt yeast partner A, B, and C
BDNF
Zuccato et al., 2001
TBP, CBP and p300/CBP-associated
factor
Huang et al., 1998;
Boutell et al., 1999;
Kazantsev et al., 1999;
Nucifora et al., 2001;
Steffan et al., 2000
(Steffan et al., 2000)
p53
Nuclear receptor corepressor and mSin3A
SP1 and TAFII130
(Boutell et al., 1999;
Jones, 1999)
Dunah et al., 2002
Apoptotic pathway
Ubiquitin conjugating enzyme
Glycolytic enzyme
Cytoskeletal, microtubule and vesicle function
Intracellular calcium binding and sensing
Non receptor signalling, protein degradation and
pre-mRNA splicing. Interaction enhanced by
lengthening of polyQ tract
Neurotrophic factor required for striatal
neuron survival
Transcription factors. May colocalize
with neuronal NIIs
Transcription factor
Mutant N-terminal Htt represses transcription from
p53 regulated promoters
Transcriptional repressor complex
Cellular localization altered in HD brain
Transcriptional activator and coactivator
Table 7 Nuclear proteins interacting with ataxins
Protein
References
Consequence of ataxin interaction
Promyelocytic leukaemia protein
Skinner et al., 1997
Leucine-rich acidic nuclear protein
Matilla et al., 1997
TBP and eyes absent protein
Perez et al., 1998
CBP
McCampbell et al., 2000;
Yvert et al., 2001;
Zander et al., 2001
(Shimohata et al., 2000)
(Yvert et al., 2001)
Wang et al., 2000
Interaction of mutant ataxin-1 with promyelocytic
leukaemia protein disrupts the nuclear matrix
Leucine-rich acidic nuclear protein expressed
specifically in the Purkinje cell. Interaction with mutant
ataxin-1 may be a determining factor in cerebellar
neurodegeneration
Recruitment to nuclear inclusions in a Drosophila
model of SCA 3. Sequestration could be involved in
cellular toxicity
Recruited to ataxin-3 and ataxin-7 containing NIIs
TAFII130
TAFII30
Homologues of yeast RAD23, a DNA
nucleotide excision repair protein.
Cone-rod homeobox protein
(La Spada et al., 2001)
factor histone acetyl transferase domains, inhibiting the enzymatic activity, which may impair gene expression. Notably, in
an in vivo Drosophila neurodegeneration model, inhibition of
histone deacetylases (HDACs) arrests the degenerative
Colocalized with NIIs in SCA 3
Colocalized with NIIs in SCA 7 transgenic mice
Mutant and wild-type ataxin-3 bind these proteins
equally well. Whether DNA repair is affected by the
expanded polyQ is unknown
PolyQ expanded ataxin-7 suppresses cone-rod
homeobox protein transactivation with effects on
cone-rod homeobox protein-regulated genes. This interaction
may account for the retinal degeneration seen in SCA 7
process (Steffan et al., 2001). Recent work in HD transgenic
mice has confirmed that inhibition of HDACs, hence
increasing the amount of acetylated histones, improves
motor impairment and increases brain histone acetylation
2394
C. M. Everett and N. W. Wood
Fig. 2 CREB/CBP-mediated gene transcription and mutant polyQ
Htt. Schematic representation of CRE-regulated genes, their
activation and interference with this process by mutant polyQ
proteins—in this case Htt. (A) CREB binds to the CRE and with
the association of CBP and TAFII130 there is activation of RNA
polymerase (Pol) and active gene transcription. (B) Mutant polyQ
Htt binds directly to CBP and TAFII130, preventing activation of
the transcription machinery. CREB, CBP and TAFII130 are also
sequestered in NIIs, reducing their availability for transcriptional
activation. A similar mechanism may be common to other polyQ
diseases.
(Ferrante et al., 2003; Hockly et al., 2003). Thus, HDAC
inhibitors may be beneficial in human disease.
Htt also interacts with the ubiquitous transcription factor
Sp1, and coexpression of Sp1 and TAFII130 in cultured striatal cells overcame the downregulation of dopamine D2 receptor gene transcription caused by mutant Htt (Dunah et al.,
2002). Interestingly, this study also showed that soluble
mutant Htt prevented Sp1 binding to DNA from both presymptomatic and HD post-mortem brain. Thus, trapping of
transcription factors within NIIs may not entirely account for
pathogenic effects of mutant Htt. Rather, gene expression may
be affected by soluble mutant Htt–transcription factor interactions. For example, TBP, CBP and SP1 remained diffusely
localized within the nucleus in HD mouse models despite the
presence of NIIs, with no difference in staining patterns
between wild-type and HD mouse brains (Yu et al., 2002).
To investigate the functional effect of transcription factor
interactions, oligonucleotide microarrays have been employed
to screen striatal mRNA in transgenic mice modelling HD.
There were diminished levels of less than 2% of the mRNAs
tested. These did, however, encode components of neurotransmitter, calcium, and retinoid signalling pathways
involved in striatal neuron function. Similar changes in
gene expression were also seen in another HD mouse
model (Luthi-Carter et al., 2000). Further, gene expression
changes in mutant atrophin-1 transgenic mice overlap with
those found in HD transgenics (Luthi-Carter et al., 2002),
suggesting common mechanisms in the neurodegenerative
process. It is becoming increasingly apparent that both
wild-type and mutant Htt have important roles in gene transcription. Consistent with this is the regulation of BDNF, a
neurotrophic factor necessary for striatal neuron survival, at
the transcriptional level by Htt. BDNF expression is downregulated in the presence of mutant Htt (Zuccato et al.,
2001). Other genes are upregulated in the presence of mutant
Htt [e.g. a ribosomal protein Rrs1 (Fossale et al., 2002)].
The mutant ataxins also have effects on gene expression.
In SCA 1 transgenic mice, six neuronal genes involved in
signal transduction and calcium homeostasis and abundantly
expressed in Purkinje cells were downregulated. This downregulation occurred before detectable pathology. Such interactions with genes important in cellular homeostasis are likely
to have toxic effects. Similar effects were also evident in SCA 1
human tissues (Lin et al., 2000). Altered RNA processing
may also play a role in the pathogenesis of SCA 1 as
in vitro ataxin-1 was found to bind to RNA in a manner
inversely related to polyQ length (Yue et al., 2001).
A Drosophila model of SCA 1 has been screened for genes
that modify neurodegeneration (Fernandez-Funez et al.,
2000). Modifiers included molecular chaperones and genes
involved in transcription and RNA processing. In a SCA 3
cellular model both upregulation and downregulation of genes
occur suggesting that loss of normal ataxin-3 as well as the
gain of function of mutant ataxin-3 may be important in
pathogenesis (Evert et al., 2003).
There have been more suggestions recently that expanded
polyQ tracts may act independently of protein context. This has
been alluded to above in relation to the toxic gain of function of
hypoxanthine phosphoribosyltransferase when an expanded
polyQ tract was introduced into this protein. For example,
polyQ expansions present in atrophin-1 and Htt transgenic
mouse constructs resulted in similar changes in gene expression, as determined by microarray analysis. Interestingly, several of the genes affected in these DRPLA and HD transgenic
mice were also affected in SCA 7 and Kennedy’s disease
mouse models (Luthi-Carter et al., 2002). Further, CAG repeat
expansions found in the junctophilin-3 and TBP genes are
associated with an HD-like phenotype (Stevanin et al.,
2003). These findings also suggest a commonality of
neurodegenerative mechanisms in these diseases.
As in HD, the interaction of the polyQ repeat containing
atrophin-1, AR and ataxins with a variety of nuclear proteins may
have important pathological consequences (Tables 4, 5 and 7).
Discussion
The pathogenesis of the polyQ repeat diseases is complex.
Certainties are the genetic defects and the association of NIIs
with disease. The aggregations may or may not be primarily
responsible for neurodegeneration. The multiple interactions
of wild-type and mutant polyQ proteins with a variety of
Trinucleotide repeats and neurodegeneration
proteins involved in diverse cellular functions could result in
cellular dysfunction, apoptosis, neurodegeneration and
disease. It remains unclear which of the multiple molecular
changes that occur in the polyQ diseases are of primary pathogenic importance and which are involved in continuation of
the pathological process. Recent work has suggested dysfunction of CREB/CBP-mediated gene expression may be a
common mechanism involved in polyQ-mediated neurodegeneration. Whether this represents a common pathway initiating the degenerative process or occurs as a result of toxicity
‘upstream’ remains to be clarified. A major challenge is to try
to collate evidence from in vitro and in vivo models and
indeed patients to further define pathogenic mechanisms
and to develop therapies. Indeed, therapies are already
being explored in HD based on evidence derived from experimental models (Beal and Ferrante, 2004).
Neurodegenerative trinucleotide repeat
diseases with untranslated repeat expansions
This class is separate to the polyQ repeat diseases and includes
SCA 8, SCA 12 and Friedreich’s ataxia (FRDA). In these, the
expanded repeat is not translated into expansion within a
mutant protein. Certainly in FRDA there is downregulation
of the frataxin gene in association with a GAA repeat expansion. There is some evidence for gene downregulation in
SCA 8. The mechanism responsible for perturbed gene
expression in these diseases remains unclear.
SCAs with untranslated trinucleotide repeats
(SCA 8 and SCA 12)
There is an expanded CTG repeat in the 30 untranslated region
of the SCA 8 gene (Koob et al., 1999). There remains debate
as to whether the expanded CTG repeat found in association
with the SCA 8 locus represents a rare associated polymorphism (Stevanin et al., 2000; Worth et al., 2000; Schols et al.,
2003) or is causative for the disease (Day et al., 2000; Cellini
et al., 2001). The CUG containing SCA 8 transcript may
represent an antisense transcript to a gene coding for an
actin organizing protein named kelch-like protein 1
(Nemes et al., 2000). The suggested SCA 8 transcript overlaps
the transcription and translation start sites of KLH1 and it is
hypothesized that the SCA 8 antisense transcript regulates
expression of KLH1, with the presence of an expanded
CUG repeat perturbing such regulation. An expanded CAG
repeat has been linked to the 50 untranslated region of the
protein phosphatase 2 regulatory subunit B gene in SCA 12
(Holmes et al., 1999).
FRDA
Nicholaus Friedreich described the disease in 1863. It is the
most common of the hereditary ataxias with a prevalence of
1 in 50 000 and is another of the untranslated trinucleotide
repeat diseases.
2395
Genetic features
FRDA is an autosomal recessive disease usually with onset
before the age of 25 (Harding, 1981). In 1996 the most
common genetic abnormality was defined as a homozygous
expanded GAA trinucleotide repeat in the first intron of
the frataxin gene located on the long arm of chromosome 9
(Campuzano et al., 1996). Frataxin itself is a mitochondrial
protein thought to be involved in iron metabolism (see below).
Expanded GAA repeats inhibit frataxin expression. Frataxin
transcription and expression are inversely proportional to the
length of the expanded GAA repeat, this being particularly true
for smaller expanded repeats (Campuzano et al., 1997). This
may explain the correlation of the severity of some clinical
features and age of onset with the shorter of the two expanded
repeats (Durr et al., 1996; Filla et al., 1996; Lamont et al.,
1997; Monros et al., 1997; Montermini et al., 1997c). The
residual expression from the allele with the shorter expansion
may be important in modulating disease severity.
The normal repeat length is less than 39 and patients generally have repeats ranging from 100 to 1700 (Cossee et al.,
1997; Montermini et al., 1997a, b, c). However, atypical
patients often have GAA repeats of similar length to patients
with more classical features (Gellera et al., 1997; Geschwind
et al., 1997; Montermini et al., 1997c). Other factors, such as
environment, modifier genes and somatic mosaicism, may all
play a role in such variation. Expanded GAA repeats are
unstable both meiotically and mitotically. The repeat tends
to contract on paternal transmission, shorter repeat arrays
being found in sperm than in leucocytes (Pianese et al.,
1997). Expansion or contraction can result following maternal
transmission (Monros et al., 1997; Pianese et al., 1997).
Approximately 2% of patients are compound heterozygotes,
with the GAA repeat expansion on one allele and a point
mutation on the other (Campuzano et al., 1996; Cossee
et al., 1999). Generally N-terminal mutations result
in milder phenotype than that seen with mutations at the
C-terminal of the protein.
The frataxin gene and GAA repeats
Frataxin mRNA is found most abundantly in heart, liver,
skeletal muscle and pancreas. Expression is tissue-pecific
and mirrors the disease distribution (Campuzano et al.,
1996; Jiralerspong et al., 1997; Koutnikova et al., 1997). In
the CNS, expression is highest in the spinal cord,with lower
levels in the cerebellum and very little expression in the cerebral cortex. Frataxin is developmentally expressed in mice
(Jiralerspong et al., 1997; Koutnikova et al., 1997) and the
frataxin knockout mouse dies in utero (Cossee et al., 2000).
Embryonic lethality of frataxin nullizygous mice can be rescued with expression of human frataxin (Pook et al., 2001).
A viable frataxin knockout mouse has been made using
conditional gene-targeting techniques (Puccio et al., 2001).
In these mice the frataxin gene has been disabled in muscle
and neural tissue, with the development of aspects of
FRDA related to the frataxin deficient tissues. In the muscle
2396
C. M. Everett and N. W. Wood
knockouts there was a hypertrophic cardiomyopathy. In the
neural knockouts progressive ataxia with neurodegeneration
in the cerebellum and dentate nucleus occurred. There was
also a sensory proprioceptive neuropathy. There was impaired
activity of the respiratory chain complex and subsequent iron
accumulation within mitochondria. These animals provide a
model to further investigate the sequelae of frataxin deficiency and in which to test possible therapies.
Mechanisms for reduced frataxin expression
in FRDA
Some inroads have been made into mechanisms underlying
GAA repeat-induced gene repression. Transient transfection
experiments, using a two-exon construct derived from the
HIV gp120 gene with 9–270 GAA repeats present in the
only intron, showed that both transcription and replication
were impaired in a manner dependent on GAA repeat length
and orientation (Ohshima et al., 1998). Pronounced stalling at
the replication fork in yeast occurs when the expanded GAA
strand serves as the lagging strand template (Krasilnikova and
Mirkin, 2004). The propensity of GAA repeats to form triplexes and the inhibitory effects on transcription of such
structures have been postulated as a possible mechanism
for the reduction of frataxin expression (Wells et al., 1988;
Ohshima et al., 1996; Mariappan et al., 1999). DNA triplexes
formed by GAA repeats have been shown to be ‘sticky’, due to
the formation of a single-stranded region within the triplex
that has the propensity to self-associate to other such strands
in other GAA triplexes. Sticky DNA may impair transcription
(Sakamoto et al., 1999). GAA repeats have been shown to
cause pausing of RNA polymerase in vitro in a length-dependent manner, due to the transient formation of an intramolecular DNA triplex initiated by RNA polymerase itself
(Grabczyk and Usdin, 2000). More recent in vitro experiments
have shown that sticky DNA is capable of impairing transcription and of sequestering RNA polymerase to the sticky repeat
(Sakamoto et al., 2001b). Therefore, a model of GAA repeatinduced transcriptional repression has been suggested, in
which sticky DNA sequesters transcription factors. Such an
effect has not been demonstrated in vivo.
A 65 GAAGGA hexanucleotide repeat, found in several
related individuals not suffering from FRDA, does not affect
transcription and expression in the gp120 reporter gene assay.
Neither triplexes nor formation of sticky DNA occurred with
this hexanucleotide repeat (Ohshima et al., 1999; Sakamoto
et al., 1999) and, as expected, transcription was not impaired
(Sakamoto et al., 2001b). Therefore, a pure GAA repeat
seems necessary to cause disease as imperfections may interfere with the pathological properties. Indeed, inclusion of
GGA imperfections in long GAA repeats reduced sticky
DNA formation dependent on the proportion of GGA imperfections in the array, relieved in vitro transcriptional repression and reduced repeat instability (Sakamoto et al., 2001a).
A GAA repeat frataxin knockin mouse has been made, with
230 GAA repeats placed in the first intron of the frataxin gene.
There was a small reduction in frataxin expression in homozygous mice, leaving a residual expression level of approximately 75% in the tissues examined. There was no associated
phenotype or accumulation of tissue iron. Compound heterozygous mice carrying both a GAA repeat expansion and a
non-functional frataxin allele were similarly unaffected,
despite frataxin expression of 25–30% of the wild-type levels
(Miranda et al., 2002). Therefore, frataxin levels of less than
25% are probably required for a phenotype to develop in mice
and a repeat expansion of more than 230 may be necessary to
repress frataxin expression to this level. Indeed, in human
FRDA lymphoblastoid cell lines, frataxin expression determined by immunoblotting ranged from 4 to 29% compared
with normal (Campuzano et al., 1997).
Recent work has shown that GAA repeats may induce gene
silencing in association with changes in the chromatin packaging of DNA. A (GAA)200 repeat expansion linked to a
human CD2 (hCD2) reporter gene in transgenic mice was
found to heritably silence expression of this gene. Since
the GAA repeat was linked to an untranscribed region of
the hCD2 transgene, the inhibitory transcriptional effects of
GAA repeats were excluded. The GAA repeat induced repression of hCD2 manifested as the phenomenon of ‘position
effect variegation’ of gene expression, in which, rather
than hCD2 expression being silenced in all cells, a proportion
of cells were silenced with the remaining cells actively
expressing hCD2. This form of gene silencing is characteristic
of that found when genes are placed near to densely packaged
chromatin (known as heterochromatin). In cells in which
hCD2 was silenced, there was condensation of chromatin
packaging at the promoter of the gene. Further, this silencing
was modified by heterochromatin protein 1b, a protein known
to be a major component of heterochromatin (Saveliev et al.,
2003). It is possible that the phenotypic variation seen in
FRDA may be due to variegation of frataxin gene expression
(Fig. 3), the degree of silencing and therefore variegation
perhaps influenced by the length of the repeat and/or by
other modifiers, for example heterochromatin protein 1b.
This work raises the possibility of therapies aimed at modifying chromatin, which may be effective in the treatment of
FRDA. For example, condensation of chromatin packaging of
DNA is associated with histone deacetylation and, as discussed above, agents are available that inhibit HDACs;
these may overcome frataxin repression in FRDA. Interestingly, in cell lines containing constructs of the entire human
FRDA functional sequence, upregulation of frataxin expression occurred with butyric acid treatment (Sarsero et al.,
2003), an agent known to be an HDAC inhibitor.
A CTG expansion behaved similarly in the above transgenic mouse model, causing gene silencing and chromatin
condensation (Saveliev et al., 2003). Other trinucleotide
repeat diseases, such as SCA 8, SCA 12 and myotonic dystrophy 1, and perhaps also extending to diseases in which
other repeats are found in untranslated regions [e.g. SCA
10 (Matsuura et al., 2000) and myotonic dystrophy 2 (Liquori
et al., 2001)], may share a similar molecular pathogenic
Trinucleotide repeats and neurodegeneration
2397
The frataxin protein
Fig. 3 Suggested mechanisms for downregulation of frataxin
expression in FRDA. A schematic representation of the frataxin
locus is shown. P is the promoter. Ex1, Ex2 represent exons 1 and
2. In1 is intron 1, containing the GAA repeat. The filled ovals
represent nucleosomes, the basic structural element of chromatin.
(A) The wild-type locus. The locus is proposed to lie in an ‘open’
chromatin environment (widely spaced nucleosomes), allowing
active gene transcription. Thus, there is expression of frataxin in
all cells. (B) Frataxin locus with an expanded GAA repeat. The
GAA repeat may cause the chromatin to ‘close’ (tightly packaged
nucleosomes), forming heterochromatin. Chromatin at the promoter may also close due to its proximity to the heterochromatin
at intron 1 (a position effect). Expression from genes close to
heterochromatin characteristically variegates (position effect
variegation). Thus, frataxin may be expressed in only a proportion
of cells. An untranscribed GAA repeat acts similarly in a
transgenic mouse model (Sareliev et al., 2003). (C) Frataxin locus
with an expanded GAA repeat. The GAA repeat may impede the
transcriptional machinery, resulting in downregulation of frataxin
expression in all cells.
mechanism. Indeed, it is known that the CTG expansion in
myotonic dystrophy 1 alters the chromatin structure of an
enhancer present in the 30 region of the myotonic dystrophy
protein kinase gene, rendering it inaccessible to transcription factors (Otten and Tapscott, 1995; Klesert et al., 1997),
and that CTG repeats are capable of efficiently recruiting
nucleosomes, the basic structural element of chromatin
(Wang et al., 1994; Wang and Griffith, 1995). Interestingly,
the genetic defect in facioscapulohumeral muscular dystrophy
(FSHD) is the deletion of subtelomeric repeats on chromosome 4. It has been suggested that these repeats normally
serve to repress nearby genes, perhaps through an effect on
chromatin packaging. With deletion of these repetitive
regions in facioscapulohumeral muscular dystrophy, the
nearby genes are suggested to become dysregulated (Gabellini
et al., 2002).
Frataxin is a mitochondrial protein of 210 amino acids and is
localized to the inner mitochondrial membrane (Campuzano
et al., 1997; Koutnikova et al., 1997). The N-terminal mitochondrial targeting sequence is proteolytically cleaved within
the mitochondrion (Koutnikova et al., 1998). The precise role
of frataxin within the mitochondrion remains unclear and
several functions have been suggested, which may not be
mutually exclusive. Studies with yeast frataxin homologue 1
protein (Yfh1p) provided the first evidence that frataxin
is involved in mitochondrial iron balance. Disrupting
Yfh1p resulted in a large mitochondrial iron excess, impairment of oxidative phosphorylation, increased sensitivity to
oxidant stress and damage to mitochondrial DNA (Babcock
et al., 1997; Wilson and Roof, 1997). Reactive oxygen species
formed within the iron overloaded Yfh1p-deficient mitochondrion are thought to be toxic to mitochondrial DNA and proteins and also to nuclear DNA (Karthikeyan et al., 2003b).
Lately, further characterization of Yfh1p has clarified its
role in iron–sulphur cluster (ISC) synthesis. ISCs are cofactors
for proteins involved in metabolic processes involving electron transfer and the mitochondrion is essential to ISC synthesis. Frataxin is a component of the ISC synthetic machinery
acting early in the process, perhaps loading the system with
iron, in concert with other proteins of the ISC assembly
mechanism e.g. Isu1, Isu2 and Nfs1 (Muhlenhoff et al.,
2002, 2003; Gerber et al., 2003). Export of iron from the
yeast mitochondrion is also dependent on ISC synthesis
(Chen et al., 2002b). Microarray analysis of gene expression
in human cells has confirmed that several genes in the
ISC biosynthetic pathway, in addition to several in the sulphur
amino acid pathway, are frataxin-dependent and in frataxindeficient cells there is downregulation of genes involved in
ISC metabolism (Tan et al., 2003).
Frataxin may be involved in the response of the cell to
oxidative stress. FRDA fibroblasts are hypersensitive to
oxidant stress and inhibitors of apoptosis and iron chelators
prevented death in these cells, suggesting that oxidative stress
induces apoptosis and hence neurodegeneration (Wong et al.,
1999). In a cell culture model of neuronal differentiation,
frataxin deficiency resulted in increased apoptosis during
neurogenesis (Santos et al., 2001). Oxidative sensitivity in
frataxin deficient lymphoblasts can be rescued by reintroduction of frataxin (Tan et al., 2001). As discussed above, in yeast
both loss of frataxin expression and chronically reduced
expression levels resulted in oxidative damage to both mitochondrial and nuclear DNA (Karthikeyan et al., 2003). Interestingly, it has been suggested that tissue specificity of
oxidative stress in frataxin deficiency may be mediated by
the high levels of cellular citrate in actively metabolizing cells
(Chen et al., 2002a; Tan et al., 2003). The sensitivity to
oxidant stress has been suggested to be secondary to defective
antioxidant defences, particularly induction of superoxide dismutase (Chantrel-Groussard et al., 2001). There may also be
overactivity of the stress kinase pathway in frataxin-deficient
2398
C. M. Everett and N. W. Wood
cells with upregulation of apoptotic caspases (Pianese et al.,
2002). Oxidative stress itself is thought to damage ISC proteins. In myocardial cells from FRDA patients there is depletion of ISC-containing subunits of respiratory complexes I,
II and III in addition to aconitase, another iron–sulphurcontaining protein (Rotig et al., 1997). Many of the currently
proposed potential treatments for FRDA are based around
antioxidants; for example, coenzyme Q10 and idebanone
(Durr, 2002).
Frataxin may also be a mitochondrial iron store. Recombinant Yfh1p forms spherical multimers, in an iron dependent
manner, of approximately 60 subunits with a molecular
weight of 1.1 mDa. The multimer is able to sequester iron
in a bioavailable form (Adamec et al., 2000). Yfh1p may keep
mitochondrial iron in a soluble, non toxic and usable form
(Adamec et al., 2000; Andreassen et al., 2000; Gakh et al.,
2002; Park et al., 2002, 2003).
Understanding the function of frataxin may provide
avenues for developing therapies. Already antioxidants are
being investigated and there are suggestions that mitochondrial iron chelators may be useful (Richardson, 2004).
Conclusions
The trinucleotide repeat diseases are a heterogeneous group of
disorders. Within the polyQ class there is a significant degree
of overlap in both clinical features and molecular pathology.
A definitive mechanism for neurodegeneration, through the
toxic gain of function of the mutant proteins in this group,
currently remains obscure.
Perhaps the untranslated repeat disorders are easier to
visualize in that the presence of a repeat expansion results
in loss of gene product and therefore disease. However, the
mechanisms underlying gene repression in this group remain
ill-defined. Whether a common mechanism for repeat-induced gene repression exists is intriguing but unknown. All
triplet repeat disorders, unfortunately have one aspect in common, this being the lack of an effective therapy to reverse or
halt the degenerative process. Perhaps the extensive
work done on these diseases will provide future therapeutic
interventions.
Note added in proof
There have been several recent publications relating to pathogenic molecular mechanisms in HD and possible treatment
targets, which are summarised briefly below. The cellular
process of autophagy is known to be involved in the clearance
of mutant Htt aggregates (Ravikumar et al., 2002). A molecule involved in the induction of autophagy (mammalian
target of rapamycin, mTOR) is sequestered within these
aggregates. This sequestration reduces its kinase activity
with consequent upregulation of autophagy and protection
against polyQ toxicity. Induction of autophagy with rapamycin protected against cell death in HD cell lines and against
neurodegeneration in a Drosophila HD model. Aggregates
were also reduced in a HD mouse model with improvement
in behavioural tasks (Ravikumar et al., 2004). Treatment of
HD with rapamycin has therefore been proposed. Interestingly, when mutant Htt was modified by SUMO-1 (small
ubiquitin like modifier-1) there was exacerbation of toxicity
in cell lines and of neurodegeneration in Drosophila (Steffan
et al., 2004) Thus, inhibition of SUMOylation may also be a
therapeutic target. There is also further evidence for the interaction of mutant Htt with the polyQ repeat of TBP, resulting in
deactivation of this transcription factor (Schaffar et al., 2004)
Additionally, the potential role for impaired axonal transport
of BDNF by mutant Htt in the pathogenesis of HD has been
highlighted (Gauthier et al., 2004).
Finally, there is additional data implicating frataxin as an
iron chaperone protein protecting aconitase from oxidantinduced inactivation and promoting activation of this mitochondrial enzyme (Bulteau et al., 2004).
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