Brain Advance Access originally published online on April 13, 2006
Brain 2006 129(6):1357-1370; doi:10.1093/brain/awl081
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Review Article |
Molecular pathogenesis of spinocerebellar ataxias
1 Institute of Child Health, University College London London, UK 2 Department of Molecular Neuroscience, Institute of Neurology, University College London London, UK
Correspondence to: Antoni Matilla Dueñas, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK and Paola Giunti, Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, WCIN 3BG. E-mail: A.Matilla{at}ich.ucl.ac.uk
 |
Summary |
|---|
 Top Summary IntroductionConcluding remarksReferences |
|---|
The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its afferent and efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly understood. Compelling evidence points to major aetiological roles for interference with transcriptional regulation, protein aggregation and clearance, the ubiquitin-proteasome system and alterations of calcium homeostasis in the neuronal loss observed during the neurodegenerative process. But novel molecular routes that might be disrupted during disease progression are also being identified. These pathways could act independently or, more likely, interact and enhance each other, triggering the accumulation of cellular damage that eventually leads to dysfunction and, ultimately, the demise of neurons through a series of multiple events. This suggests that simultaneous targeting of several pathways might be therapeutically necessary to prevent neurodegeneration and preserve neuronal function. Understanding how dysregulation of these pathways mediates disease progression is leading to the establishment of effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the current therapeutic strategies.
Key Words: spinocerebellar ataxias; cerebellum; neurodegenerative disorders; neurodegenerative mechanisms; therapy
Abbreviations: ADCA, autosomal dominant spinocerebellar ataxia; CAG, DNA sequence coding for glutamine; DRPLA, dentatorubral pallidoluysian atrophy; ER, endoplasmic reticulum; FGF14, fibroblast growth factor 14; HDACs, histone deacetylases; KCNC3, potassium voltage-gated channel subfamily C member 3; PP2, protein phosphatase 2 (formerly 2A); PRKCG, protein kinase C, gamma; Q, glutamine; SCA, spinocerebellar ataxia; SPTBN2, beta-III spectrin; TBP, TATA box binding protein; UPS, ubiquitin-dependent proteasome system
Received December 7, 2005. Revised February 28, 2006. Accepted March 2, 2006.
|
Introduction |
|---|
|
TopSummaryIntroductionConcluding remarksReferences |
|---|
The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders characterized by progressive cerebellar ataxia of gait and limbs variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy and peripheral neuropathy (Zoghbi, 2000
). Disease onset is usually between 30 and 50 years of age, although early onset in childhood and onset in later decades after 60 years have been reported. The prognosis is variable depending on the underlying cause of the spinocerebellar ataxia subtype. Epidemiological data indicate that SCAs might be more common than that previously estimated with prevalences of up to 5–7 in 100 000 in some populations (van de Warrenburg et al., 2002; Craig et al., 2004). This is similar to the prevalence of other uncommon motor neurodegenerative diseases, such as Huntington's or motor neuron diseases. Founder mutation effects appear to contribute to the variable prevalence detected in specific SCA subtypes.
In the pre-genomic era, SCAs have been particularly controversial in terms of nomenclature and classification. Harding first proposed a classification of the autosomal dominant cerebellar ataxias (ADCAs) on the basis of the clinical symptoms, and differentiated this group of disorders into three main groups (Table 1) (Harding, 1993). It is important to note that Harding's classification has not been overridden by the genetic classification and is still invaluable as a guideline in clinical practice and to prioritize genetic tests for diagnosis. ADCA type I is characterized by ataxia of the gait variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, cognitive impairment, optic atrophy or peripheral neuropathy. The clinical features in this group of ataxias are caused by a combination of degeneration of the cerebellum, basal ganglia, cerebral cortex, optic nerve, pontomedullary systems, spinal tracts or peripheral nerves. ADCA type II is distinct from ADCA type I by the presence of pigmentary retinopathy. A third group, ADCA type III, includes relatively pure cerebellar ataxias where the degenerative process is limited to the cerebellum. ADCAs I and III are clearly genetically heterogeneous, whereas at least two different genes are associated with ADCA II (Table 1) (Giunti et al., 1999). Although the aetiology of SCAs is still poorly understood, genetic analyses, epidemiological data, neuropathological investigations and new experimental models are providing important new insights into the pathogenic mechanisms. At least 28 distinct loci are responsible for rare Mendelian forms of SCA (Table 2). Interestingly, a few SCA subtypes, including SCAs 1, 2, 3, 6, 7, 17 and dentatorubral pallidoluysian atrophy (DRPLA), are caused by the expansion of a CAG (DNA sequence coding for glutamine) repeat sequence located within the coding region of specific genes, leading to an abnormally long polyglutamine (polyQ) tract in the encoded proteins named ataxins 1, 2 and 3, alpha 1A-voltage-dependent calcium channel, ataxin 7, TATA box binding protein (TBP) and atrophin 1, respectively. These SCAs show, as common features, the progressive neurodegeneration of neuronal subsets in distinct brain areas and the formation of polyQ-containing protein aggregates forming characteristic nuclear or cytoplasmic inclusions (Zoghbi and Orr, 2000). The age at onset and severity of disease symptoms inversely correlate with the length of the glutamine repeat. A second group of SCAs, including SCAs 8, 10 and 12, are caused by a repeat expansion located outside of the coding region of the disease genes leading to dysregulation of gene expression (Table 2) (Holmes et al., 1999; Koob et al., 1999; Matsuura et al., 2000). While the molecular mechanisms underlying SCAs 8 and 10 are unclear, SCA12 appears to be caused by dysregulation of the activity of the crucial enzyme protein phosphatase 2 (PP2, formerly named PP2A) in cerebellar Purkinje cells. Different mechanisms cause cerebellar ataxia and neurodegeneration in SCAs 5, 13, 14 and 27, where alterations in amino acid composition in beta-III spectrin (SPTBN2) (Ikeda et al., 2006), potassium channel KCNC3 (Waters et al., 2006), protein kinase C (PRKCG) (Chen et al., 2003a; Yabe et al., 2003) and fibroblast growth factor 14 (FGF14) (van Swieten et al., 2003), respectively, elicit disease symptoms in these four SCA subtypes. In the rest of SCAs, the genes and, therefore, the mutations remain to be identified and characterized. Understanding the pathogenetic mechanisms of neurodegeneration in spinocerebellar ataxias should lead to the identification of potential therapeutic targets and ultimately facilitate drug discovery.
|
|
This review highlights the scientific evidence for the major pathways leading to neurodegeneration in autosomal dominant SCAs, generated from genetic analysis, in vitro studies, experimental animal models and post-mortem brain studies (Fig. 1). We discuss the convergence of these pathways in the identification of potential molecular targets that could be used effectively to develop treatment (Table 3).
|
|
Polyglutamine neurotoxicity: protein aggregation, misfolding, stability and clearance
Seven spinocerebellar ataxia subtypes including SCAs 1, 2, 3/Machado-Joseph disease, 6, 7, 17 and DRPLA are caused by the expansion of a CAG-repeat sequence in specific genes, leading to abnormally long polyQ tracts in the encoded proteins (Zoghbi and Orr, 2000
). Presumably, a similar pathogenic pathway is involved in these SCAs, since each of the expanded CAG repeats encodes polyglutamine and the pathogenic threshold for disease is roughly the same, at around 40 copies of the repeat in most of the different subtypes. It is assumed that the common toxic gain-of-function mechanisms for the polyglutamine-containing protein are aggregation and deposition of misfolded proteins leading to neuronal dysfunction and eventually cell death. Proteins with expanded stretches of polyglutamine appear to take on an abnormal configuration resulting in the formation and deposition of polyglutamine aggregates in disease neurons forming characteristic nuclear or cytoplasmic inclusions, which are neuropathological hallmarks in these diseases (Ross and Poirier, 2004). These inclusions contain cellular components such as ubiquitin, the proteasome, HSP70 and transcription factors (Cummings et al., 1998; McCampbell et al., 2000; Schmidt et al., 2002). Whether the toxicity is a direct result of the aggregate or results from intermediary structures formed during the process of aggregation remains to be determined. However, blocking aggregation has been one approach attempted to minimize toxicity. Expanded polyglutamine proteins form fibrillar proteinaceous aggregates much more rapidly than normal proteins (Chow et al., 2004). Therefore, a possible mechanism for aggregate formation by the mutant protein would be by loss of native state stability by the expanded polyglutamine and, thus, leading to the formation and accumulation of a partially unfolded, aggregation-prone species, resulting in fibrillization. This phenomenon might account for the earlier age of onset and higher severity of disease symptoms observed when mutant ataxins contain longer numbers of glutamines. Enigmatically, despite the fact that the majority of the proteins associated with spinocerebellar neurodegenerative disease are expressed systemically, the resulting cytotoxicity appears restricted to a few neuronal subtypes of the CNS. Selective cellular conditions and specific protein–protein interactions might confer local insoluble conditions leading to oligomerization and fibrillization in vulnerable neurons.
The relationship between SCA neurodegeneration and the ubiquitin-dependent proteasome system (UPS), the main cellular machinery to degrade aberrantly folded proteins, is evidenced by the consistent findings of ubiquitin-positive protein aggregates in neuropathological studies (Ross and Poirier, 2004). In addition, there is evidence that a few ataxins, such as ataxins 1, 3 and 7, are susceptible to be ubiquitinated and targeted by the proteasome for degradation and clearance (Cummings et al., 1999; Matilla et al., 2001; Chai et al., 2004). Protein misfolding exerted by the expanded polyglutamine might lead to difficulties in the recognition and degradation process by the proteasome and, hence, in subsequent impaired clearance of mutant proteins. Further evidence indicates that polyglutamine expansions and aggregates may also derange UPS function. For instance, polyglutamine-expanded ataxin 1 appears to decrease the activity of the proteasome in cell culture (Park et al., 2005). In SCA3, ataxin 3 is an ubiquitin-specific cysteine protease that associates with the proteasome (Chai et al., 2004; Nicastro et al., 2005). It de-ubiquitinates proteins by binding polyubiquitin chains through several ubiquitin interaction motifs (UIMs) within the Josephin domain, which is located near the polyQ tract. Elucidation of the molecular structure of the Josephin domain within ataxin 3 has led to the proposal of a model for recognition of interactions and formation of stable complexes with HHR23B located in the same surface involved in the interaction with UBA domains, the S5a polyUb-binding site and the proteasome (Nicastro et al., 2005). These observations provide a link between ataxin 3 and the UPS that is of particular relevance to neurodegenerative diseases. The expanded polyglutamine within ataxin 3 might alter its normal function and produce functional disruptions of the UPS pathway. Alternatively, reduction of proteasome activity may result from caspase-dependent cleavage of proteasome subunits owing to aggregated protein-induced apoptosis (Sun et al., 2004). Since the UPS plays a prominent role in the detoxification and targeting of damaged proteins for degradation, failure of this system might lead to an abnormal accumulation of a variety of toxic proteins, including those containing the polyglutamines, that would otherwise have been degraded, ultimately leading to neuronal dysfunction and/ordeath. Molecular chaperones, proteins that can repair or facilitate proteasome degradation of abnormally folded proteins, may play a role in SCAs as aggregates in human post-mortem tissue often immunostain for chaperones (Ross and Poirier, 2004). This evidence indicates that the mechanisms of cell survival mediated by the endoplasmic reticulum (ER) chaperones and the unfolded protein response (UPR) are activated during neurodegeneration in spinocerebellar ataxias. The presence of unfolded proteins in the ER can cause ER stress or an imbalance between the load of unfolded proteins and the capacity of the ER protein-folding machinery. In order to restore ER homeostasis, neurons activate the ER stress response or UPR, eventually leading to transcriptional activation of genes encoding for chaperons. Consistent with this hypothesis, experimental overexpression of molecular chaperones modulates the formation of protein aggregates in cultured cells, transgenic mice and fruit flies, diminishing the toxicity of glutamine expansions (Cummings et al., 1998; Cummings et al., 2001; Bonini, 2002). How do chaperones modulate protein toxicity? A possible mechanism could be by stabilizing the misfolded monomeric conformation; chaperones might prevent the intramolecular transition that gives rise to spherical and annular oligomers and, simultaneously, stabilize a conformation that promotes inclusion body formation (Sakahira et al., 2002). Alternatively, by interacting with the disease protein, chaperones might prevent abnormal interactions with other proteins in the cell that are causal in toxicity.
Proteins that remain misfolded are degraded primarily by the ubiquitin-proteasome system, but also by the phagosome–lysosome system, a cellular process known as autophagy, which contributes to the routine turnover of cytoplasmic components (Shintani and Klionsky, 2004). Paradoxically, autophagy is used to protect cells, but also contributes to cell death. The accumulation of autophagic vesicles (bodies) has been observed in many neurodegenerative diseases where the associated proteins misfold and aggregate. Recent evidence has demonstrated that autophagy plays an essential role in the cellular clearance of toxic aggregated proteins in a cell culture model of polyglutamine-expanded ataxin 1-mediated neurodegeneration (Iwata et al., 2005). The precise mechanism by which aggregated mutant ataxin 1 is captured by autophagosomes is unclear, but it appears that inhibition of mTOR, a negative regulator of autophagic clearance, induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of neurodegeneration (Ravikumar et al., 2004). This study has established that autophagy efficiently degrades cytoplasmic insoluble aggregates and points to a possible therapeutic strategy by modulating the autophagic process to promote clearance of aggregated disease proteins. It is important to note that autophagy may also induce cell death in neurons that accumulate protein aggregates in a way that results in a pathological condition, although at present the mechanisms are unknown.
In 1993, a hypothesis was proposed where the neuronal protein inclusions induced by the expanded polyglutamines were stabilized by isopeptide cross-links introduced by transglutaminase (Green, 1993; reviewed in Hoffner and Djian, 2005). It was postulated that, as a result of excessive glutamine reiteration, the mutant proteins would become substrates of transglutaminase. Indeed, in vitro experiments demonstrated later that a glutamine repeat, if exposed on the surface of a protein, should form cross-linked aggregates in the presence of any transglutaminase activity activated by Ca2+. While it has not been easy to examine for transglutaminase activity, the treatment of cultured cells bearing a truncated atrophin 1 in the presence of the transglutaminase inhibitor cystamine reduced aggregate formation and cell death (Igarashi et al., 1998). These observations provide arguments in favour of the transglutaminase hypothesis.
Alterations in calcium homeostasis
Alteration of calcium homeostasis plays a central role in apoptosis, and Ca2+ overload or perturbation of intracellular Ca2+ compartmentalization has long been recognized to be potentially cytotoxic (Orrenius et al., 2003). Calcium storage and signalling, as well as folding, modifying and sorting of newly synthesized proteins are among the main functions of the ER in mammalian cells. Disturbances in any of these functions can lead to the so-called ER stress. Both Ca2+ overload and depletion of the ER Ca2+ pool or alterations in the Ca2+ transport systems can result in changes in protein folding, in ER stress and activation of pro-apoptotic pathways. Mitochondria are known to participate actively in intracellular Ca2+ compartmentalization (Petersen, 2002). It has become apparent that mitochondrial calcium fluxes are integrated parts of cellular Ca2+ signalling. Calcium regulates outer mitochondrial membrane (OMM) permeabilization and, therefore, release of pro-apoptotic mitochondrial proteins into the cytoplasm, such as cytochrome c and apoptosis inducing factor (AIF), which is coupled to a stress response process known as inner-membrane permeability transition.
Strong evidence points to derangements of neuronal calcium signalling in neurodegeneration of spinocerebellar ataxias. Cerebellar Purkinje cells seem to be particularly sensitive to fluxes in intracellular calcium levels, which could result from different sources, such as the reduction of chaperone activity and ER stress. Several neuronal genes abundantly expressed in Purkinje cells that are involved in calcium signalling or homeostasis are downregulated in the cerebellum of SCA1 mutant mice before the occurrence of detectable motor impairment or pathology (Lin et al., 2000; Serra et al., 2004). This suggests a major role of disruption of calcium homeostasis in cerebellar Purkinje cells that could be importantly involved in the pathogenic process and/or the survival of these cells in SCA1.
In SCA6, Purkinje cell degeneration is associated with polyglutamine expansions within the CACNA1A gene (Zhuchenko et al., 1997). The CACNA1A gene encodes an alpha (2.1) subunit, formerly named [alpha]1A, which is the major pore-forming subunit of the CaV2.1 voltage-dependent P/Q-type calcium channel (Pietrobon, 2002). Voltage-dependent calcium channels are made up of beta and gamma-s accessory subunits. Alpha subunits are membrane glycoproteins of 
2400 amino acids in length in which primary structure predicts the presence of four homologous domains, each consisting of six transmembrane domains and a pore-forming P loop. P/Q-type calcium channels are high-voltage-activated calcium channels found primarily in neurons and expressed at high levels in granule cells and Purkinje cells of the cerebellar cortex. Their principal role is believed to be in synaptic transmission. It remains to be demonstrated whether the action of the mutant gene product is to perturb calcium channel function, to serve as a target for transaminases or to bind to nuclear-binding proteins. Interestingly, three allelic diseases are caused by different types of mutations in the CACNA1A gene including SCA6, episodic ataxia type 2 and familial hemiplegic migraine (Mantuano et al., 2003). One form of cerebellar ataxia associated with a G293R mutation in the P loop of the first domain of the CaV2.1 channel has a very similar phenotype to that of SCA6 associated with CAG-repeat expansions. As point mutations within the CACNA1A gene are not likely to act via the hypothetical nuclear-binding mechanisms or have any effects on transamination, an alteration of calcium channel function might be a possible scenario for the pathogenic alleles. Polyglutamine expansions in SCA6 might interfere with the Ca2+ channel to reduce Ca2+ influx and impaired function of the mutant Ca2+ channels, rendering them incapable of preventing cell death (Matsuyama et al., 2004). Still more electrophysiological studies are needed to clarify the molecular mechanisms underlying disease pathogenesis in SCA6 and other related ataxias.
Mitochondrial stress and apoptosis
Multiple lines of evidence suggest that neuronal death in spinocerebellar ataxias might result from the direct activation of apoptotic pathways (Lipinski and Yuan, 2004). In addition to the role of mitochondria in intracellular calcium homeostasis as discussed earlier, polyglutamine-expanded cellular death of cerebellar neurons by ataxins 3 and 7 in SCA3 and SCA7, respectively, is preceded by recruitment of caspases into polyQ aggregates. This is followed by activation of caspases 3 and 9, and of mitochondrial apoptotic pathways mediated by members of the Bcl-2 family, such as Bax and Bcl-x(L) (Chou et al., 2006; Wang et al., 2006). Both factors are known key components of neuronal apoptosis by regulating mitochondrial release of cytochrome c and Smac/DIABLO. Consistent with these observations, mutant ataxin 7 in SCA7 induces translocation of cytochrome c and Smac/DIABLO to the cytosol preceded by activation of caspases 9 and 3. This suggests that mutant ataxin 7 causes apoptotic death of cerebellar neurons by promoting mitochondrial release of cytochrome c and Smac/DIABLO. Alternatively, pro-apoptotic pathways could be activated by displacement of harmful factors sequestered by expanded polyglutamines, or through non-canonical mechanisms of caspase activation. In any case, the toxic proteins may promote mitochondrial dysfunction and increased free radical production associated with oxidative damage, and abnormal energy metabolite concentration and utilization. Further evidence of mitochondrial dysfunction resulting or contributing to ataxia is exemplified by diseases caused by mutations in polymerase gamma resulting in predominant cerebellar dysfunction/atrophy. While relevant, these mechanisms of toxicity do not explain for the time being the selective vulnerability of distinct cell types and brain regions in spinocerebellar neurodegenerations.
Emerging pathways
Most of the pathways leading to toxicity by disease proteins in spinocerebellar ataxias remain to be discovered. Increasing evidence reveals that nuclear expression of polyglutamine-expanded proteins is an essential step in polyglutamine pathogenesis, and that the resulting transcriptional dysregulation caused by ataxins containing expanded polyglutamine results in neuronal dysfunction and death. Interference with gene expression would occur by the effects of the mutation exerted on the interaction with transcriptional regulatory proteins. For instance, ataxin 1 interacts with the transcriptional co-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) through the AXH domain within Atxn1 (Tsai et al., 2004). Since SMRT regulates the expression of the retinoid and thyroid hormone receptors, it is feasible that the mutant form of ataxin 1 might exert deleterious effects on SMRT-dependent transcriptional pathways. Similarly, ataxins 3 and 7, and the SCA17 and DRPLA gene products, TBP and atrophin 1, respectively, are directly involved in transcription as components of transcriptional regulatory complexes (Shimohata et al., 2000; Li et al., 2002; Zhang et al., 2002; Helmlinger et al., 2004). But the genes and pathways regulated by these factors remain unknown. Transcriptional dysregulation might account for the cell-type specificity degeneration observed in spinocerebellar ataxias, through the sequestration of factors, by long glutamine stretches within the mutant proteins, whose expression is confined to cells that degenerate in these conditions. Therefore, they would then become unavailable to perform their normal cellular duties with potentially lethal consequences. In SCA1, sequestration of the acidic nuclear protein 32 (Anp32a/Lanp) (Matilla et al., 1997), PQBP-1 (Okazawa et al., 2002), Boat (Mizutani et al., 2005) and Gfi-1/Senseless (Tsuda et al., 2005) might lead to selective cerebellar neurodegeneration by impairing transcription and dysregulating gene expression in specific cells. Remarkably, Anp32a/Lanp is a potent specific regulator of PP2 activity and its expression is predominantly confined to cerebellar Purkinje cells (Matilla and Radrizzani, 2005). Therefore, dysregulation of PP2 activity is a likely scenario underlying cerebellar neurodegeneration in SCA1. Accordingly, in both SCA1 and SCA12, cell death might be provoked by similar pathogenic mechanisms. Similarly, inactivation of the tissue-specific transcription factor CRX in SCA7 by the polyglutamine-based association with mutant ataxin 7 could contribute to the cone-rod dystrophy observed in SCA7 mice and patients (La Spada et al., 2001). One group of nuclear proteins that bind to and whose activity may be altered by mutant ataxins is histone acetyltransferases (HATs). HATs are responsible for the acetylation of histones and several other important proteins, and this modification results in altered function of the target protein (Kouzarides, 2000). HATs also regulate cellular processes at levels as different as modifying transcriptional competence of chromosomes, temporal regulation of promoter activity and protein activation/inactivation. The altered balance between protein acetylation and deacetylation may be a key process contributing to pathogenesis induced by mutant proteins containing expanded polyglutamines (Steffan et al., 2001). Importantly, restoration of this balance is possible by genetic or pharmacological reduction of the opposing enzyme group, that is, the histone deacetylases (HDACs). This is leading to new therapeutic strategies with histone deacetylase inhibitors (HDACis) to treat neurodegeneration (McCampbell et al., 2001; Steffan et al., 2001; Hockly et al., 2003).
Emerging lines of evidence highlight the importance of understanding the normal function of the disease proteins associated with spinocerebellar ataxias to unravel the molecular mechanisms underlying the detrimental effects of the mutations. In SCA1, expansion of the polyglutamine tract or nuclear expression alone is not sufficient to cause disease. It appears that phosphorylation of a specific serine residue in ataxin 1 by protein kinase B/Akt plays a crucial role in modulating the ability of the mutant form of ataxin 1 to induce neurodegeneration by influencing its biological interactions with other proteins and the formation of nuclear inclusions (Chen et al., 2003b). Therefore, the protein context and the cellular proteins with which ataxin 1 normally interacts are likely to be important in the disease process, indicating that, for instance, blocking the phosphorylation events could be a viable treatment. In support of this, the protein context appears to be a modifying factor of the age of onset of spinocerebellar degeneration (van de Warrenburg et al., 2005). In SCA2, ataxin 2 contains an RNA-binding Lsm domain characterized by a conserved sequence motif consisting of two short segments known as Sm1 and Sm2, which are separated by a variable linker (Albrecht et al., 2004). Lsm domain proteins are involved in a variety of essential RNA-processing events including RNA modification, pre-mRNA splicing and mRNA decapping and degradation, and some of them are also important components of spliceosomal small nuclear ribonucleoprotein (snRNPs) complexes (He and Parker, 2000). Interestingly, ataxin 2 interacts with A2BP1 (ataxin 2 binding protein 1) (Shibata et al., 2000), whose RNA-binding Caenorhabditis elegans homologue, fox-1, regulates tissue-specific alternative splicing (Jin et al., 2003). Deciphering the mechanisms by which ataxin 2 regulates alternative splicing should provide insights into the pathways dysregulated during disease progression leading to the identification of potential therapeutic targets.
RNA-mediated neurotoxicity has been implicated in SCA8 pathogenesis. It seems that the SCA8 gene is transcribed as a part of an untranslated RNA that overlaps with the transcription and translation start sites and the first splice junction of KLHL1, a gene that encodes a protein with structural similarities to a family of factors involved in the organization of the cytoskeleton (Koob et al., 1999). Since the SCA8 gene functions as a gene regulator, it has been proposed that a RNA gain-of-function mechanism might underlie neurodegeneration in SCA8 as is the case for myotonic dystrophy (DM) (Philips et al., 1998; Liquori et al., 2001). Genetic screens in flies have revealed that mutations in staufen, muscle-blind, split ends and CG3249 modulate neurodegeneration (Mutsuddi et al., 2004). These observations suggest that CUG expansions in SCA8 might alter associations with specific RNA-binding proteins. It is important to note that the molecular defect in SCA8 is subject of controversy, since expansions in the SCA8 gene are not exclusively detected in patients with spinocerebellar ataxia (Worth et al., 2000; Corral et al., 2005).
SCA10 is uniquely caused by an intronic pentanucleotide ATTCT repeat within the E46L gene, now designated ATXN10 (Matsuura et al., 2000). The E46L protein is widely expressed throughout the brain, contains two armadillo (arm) repeat domains and interacts with the heterotrimeric GTP-binding protein (G-protein) (Lin and Ashizawa, 2005). It has been proposed that E46L enhances heterotrimeric G-protein signalling to mediate neurite formation. E46L belongs to the armadillo repeat family of proteins where the arm repeats mediate protein–protein interactions to modulate a myriad of cellular processes, including intracellular signalling, cytoskeletal regulation, nuclear transport and regulation of gene expression both during development and throughout adult life (Coates, 2003). Therefore, E46L might be regulating important cellular processes through the mediation of G-protein intracellular signalling.
An expanded CAG trinucleotide repeat located within the promoter region of the gene encoding a brain-specific regulatory subunit of the PP2 (formerly 2A) (PPP2R2B) has been associated with SCA12 (Holmes et al., 1999). Neurodegeneration in SCA12 is confined to the cerebellum. The serine/threonine PP2 regulates a wide array of cellular processes including cell growth and differentiation, DNA replication, cellular morphogenesis, long-term depression and apoptosis (Sontag, 2001). It has been proposed that the SCA12 repeat expansion may alter the levels of expression of one splice variant (termed B beta1) of PPP2R2B by influencing the efficiency of the promoter driving expression, with potentially lethal consequences. It remains possible that the SCA12 expansion could also have an effect on PPP2R2B splicing, or alter gene expression in some other fashion. Thus far, there is little evidence to suggest that the repeat is translated into polyglutamine. PP2 dephosphorylates a diversity of kinases, including PKB/Akt and PKCs, which appear to mediate in neurodegenerative processes in SCAs 1 and 14, respectively (Chen et al., 2003a, b). Interestingly, dysregulation of PP2 promotes tau hyperphosphorylation, microtubule destabilization, modification of synapse structure and neurodegeneration in Alzheimer's disease (Lim and Lu, 2005). And significantly, the levels of PP2 activity are decreased in Alzheimer's disease. Therefore, disruption of normal brain/cerebellar PP2 functions could be a common player in the pathogenic mechanisms of neurodegenerative conditions.
The disease symptoms in SCAs 14 and 27 are elicited by alterations in amino acid composition within the gamma subunit of protein kinase C (PRKCG) (Chen et al., 2003a; Yabe et al., 2003) and FGF14 (van Swieten et al., 2003), respectively. These alterations appear to dysregulate protein function and specific cellular pathways. Calcium-phospholipid-dependent protein kinase C comprises a family of enzymes that transduce the plethora of signals promoting lipid hydrolysis, thus regulating a variety of cellular processes, such as membrane-receptor signal transduction, control of gene expression and synaptic plasticity (Newton, 2001). PRKCG is highly expressed in brain and spinal cord, with particularly high expression in Purkinje cells of the cerebellar cortex during dendritic development, where it seems to act as a negative regulator of dendritic growth and branching (Schrenk et al., 2002). Mutant PRKCG gene products are less stable than the normal protein leading to abnormal activation patterns, altered membrane targeting and enhanced activity. It is speculated that the SCA14 phenotype results from gain-of-function mechanisms rather than haploinsufficiency, because no chain-terminating mutations have been found and heterozygous PKC-null animals are neurologically normal (Abeliovich et al., 1993). However, a dominant-negative mechanism cannot be ruled out at this time. Alterations in protein stability of FGF14 underlie neurodegeneration of the cerebellum and basal ganglia in SCA27 (van Swieten et al., 2003). FGF14 is a member of a subclass of fibroblast growth factors that is expressed in the developing and adult central nervous system, and has been implicated in neuronal signalling, axonal trafficking and synaptosomal function (Wang et al., 2002). Neuropharmacological studies in mice showed that FGF14-deficient mice have reduced responses to dopamine agonists indicating that FGF14 is required for striatopallidal-mediated dopaminergic signalling. Therefore, dysfunction of this pathway could account for the cortical hyperexcitability and the parkinsonism-associated symptoms in SCA27.
More recently, the genetic defects have been identified in three spinocerebellar ataxias. In-frame deletions in the beta-III spectrin gene SPTBN2 co-segregate with SCA5 in American and French families (Ikeda et al., 2006). It appears that these spectrin mutations alter the levels, distribution and stability of the beta-III spectrin-associating protein and Purkinje cell-specific glutamate transporter EAAT4. In a German family, missense mutations within the SCA5 gene co-segregating with the disease in affected individuals may disrupt the ability of spectrin to bind to the actin cytoskeleton. These observations suggest that disruption of glutamate signalling and vesicle trafficking may play a role in the pathogenic mechanisms in SCA5, which are pathways previously implicated in neurodegeneration in SCA1, Alzheimer and Huntington's diseases and amyotrophic lateral sclerosis. In SCA13, missense mutations in exon 2 of the potassium channel KCNC3 gene have been found associated with neurodevelopmental and neurodegenerative phenotypes (Waters et al., 2006). KCNC3 (also known as Kv3.3) is a fast-rectifying voltage-gated Shaw subtype potassium channel abundantly expressed in the cerebellum, and the mutations appear to impair channel activity, being consistent with a dominant-negative effect of the mutant allele. It appears that the channel mutations shift the activation curve in the negative direction and slowed channel closing and, therefore, might change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. A single-nucleotide substitution in the 5' untranslated region of the gene encoding the Purkinje cell atrophy associated protein puratrophin 1, also known as pleckstrin homology domain, containing family G (with RhoGef domain) protein 4 (PLEKHG4), a protein implicated in intracellular signalling and actin dynamics at the Golgi apparatus, is associated with a spinocerebellar ataxia subtype characterized by pure cerebellar atrophy and sensorineural hearing impairment (Ishikawa et al., 2005). Interestingly, the puratrophin 1 gene is located on the same chromosomal region where the SCA4 gene localizes (Flanigan et al., 1996). Although the heterozygous C/T single-nucleotide substitution within the puratrophin 1 gene detected in the chromosome 16q22.1-linked ADCA Japanese families are not present in the German SCA4 family (Zuehlke and Hellenbroich, personal communication), the puratrophin 1 gene cannot be excluded from being associated with disease symptoms in SCA4 at this time.
Although ataxia is the prominent symptom, few mutations cause an almost pure cerebellar syndrome and isolated degeneration of the cerebellar cortex. On the contrary, most SCAs are multisystemic disorders showing neurodegeneration not only in the spinocerebellar tracts but also in the basal ganglia and midbrain (Schols et al., 2000). Parkinsonism symptoms in SCA1 (Gilman et al., 1996), SCA2 (Infante et al., 2004; Simon-Sanchez et al., 2005), SCA3/MJD (Gwinn-Hardy et al., 2001), SCA6 (Khan et al., 2005), SCA17 (Gunther et al., 2004) and SCA27 (van Swieten et al., 2003) are indicative of possible impairment of striatonigral and/or striatopallidal projections in these spinocerebellar ataxia subtypes.
Alterations in glutamate synaptic neurotransmission have been proposed as a possible mechanism mediating neurodegeneration. In SCA1 transgenic mice, motor dysfunction precedes neuronal death, demonstrating that mutant ataxin 1 produces disruption of motor function in SCA1 not by killing cells but by affecting some Purkinje cellular functions including alterations in synaptic plasticity (Clark et al., 1997). Elevated intracellular calcium levels by calcium-permeable glutamate receptors are suggested as a possible mechanism (Serra et al., 2004). The importance of maintaining proper glutamate transmission in the Purkinje cell/parallel fibre synapse for proper motor function is supported by studies with ataxia mouse mutants. For instance, mice lacking mGluR1 display significant motor deficits, and introduction of mGlur1 expression into Purkinje cells of mGluR1–/– mice restores normal motor function (Ichise et al., 2000).
Therapeutic strategies
There are currently no known effective treatments to modify disease progression in any of the SCAs or related neurodegenerative disorders, although some benefits on ataxic symptoms have been reported in a few therapeutic trials. A preliminary open trial with acetazolamide temporarily reduced the severity of symptoms in SCA6 (Yabe et al., 2001). Dopaminergic and anticholinergic drugs have been used to alleviate tremor, bradykinesia or dystonia in SCA2 and SCA3 (Buhmann et al., 2003; Nandagopal and Moorthy, 2004). Spasticity in SCAs could be effectively treated with baclofen, tizanadine or mimentine. In selected cases where other treatments have failed, botulinum toxin has been successfully used to treat dystonia and spasticity. Intention tremor has been ameliorated with benzodiazepines, ß-blockers or chronic thalamic stimulation (Pirker et al., 2003). Muscle cramps, which are often present at the onset of the condition in SCAs 2, 3, 7 and DRPLA are alleviated with magnesium, chinine or mexiletine. Preliminary data from a recent open trial with gabapentin have shown improvement of cerebellar symptoms in ataxia patients by increasing GABA concentration in the central nervous system and, thus, by stimulating GABAergic neurotransmission (Gazulla et al., 2004).
Innovative approaches, such as RNA interference (RNAi) with the aim of inhibiting polyglutamine-induced neurodegeneration, prevention of protein misfolding and aggregation by overexpression of chaperones, and regulation of gene expression by application of HDACis, are proving effective in pre-clinical trials. In SCA1, intracerebellar injection of vectors expressing short hairpin RNAs profoundly improves motor coordination, restores cerebellar morphology and resolves characteristic ataxin 1 inclusions in Purkinje cells of transgenic mice (Xia et al., 2004). While these results prove that RNAi therapy improves cellular and behavioural characteristics in pre-clinical trials, its application in patients to protect or even reverse disease phenotypes shall be delayed until proper toxicity tests are assessed. Pointing to a different target, molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins. Many studies have analysed the effects that chaperone overexpression has on inclusion body formation and toxicity of pathogenic polyQ fragments in cell culture, and it is clear that overexpression of molecular chaperones might prove beneficial for the treatment of neurodegenerative diseases (Muchowski and Wacker, 2005). They prevent inappropriate interactions within and between non-native polypeptides, enhance the efficiency of de novo protein folding and promote the refolding of proteins that have become misfolded as a result of the mutations and cellular stress (Chan et al., 2000). Chemical and molecular chaperones might also prevent toxicity by blocking inappropriate protein interactions, by facilitating disease protein degradation or sequestration or by blocking downstream signalling events leading to neuronal dysfunction and apoptosis. Congo Red, thioflavine S, chrysamine G and Direct Fast have proved effective in suppressing aggregation in vitro and in vivo (Heiser et al., 2000; Sanchez et al., 2003). Several low molecular mass compounds, such as the organic solvent dimethylsulphoxide (DMSO) and the cellular osmolytes glycerol, trimethylamine N-oxide and trehalose, increase the stability of proteins in their native conformation; hence they are called chemical chaperones on the basis of their influence on protein folding. They are effective in preventing cell death triggered by mutant ataxin 3 (Yoshida et al., 2002). Trehalose was identified in an in vitro screen for inhibitors of polyQ aggregation, and its administration reduces brain atrophy, improves motor dysfunction and extends the lifespan of mice resembling the polyglutamine disorder Huntington's disease (Tanaka et al., 2004). In vitro experiments suggest that the beneficial effects of trehalose result from its ability to bind and stabilize polyglutamine-containing proteins. More recently, a new generation of small chemical compounds that directly target polyQ aggregation without significant cytotoxicity have been identified in high-throughput screens using cell-free assays or by targeting cellular pathways (Heiser et al., 2002; Zhang et al., 2005). These compounds inhibit polyQ aggregation in cultured cells and intact neurons and can rescue polyQ-mediated neurodegeneration in vivo. By a different mechanism, a small molecule that acts as a co-inducer of the heat-shock response by prolonging the activity of heat-shock transcription factor HSF1, arimoclomol, significantly improves behavioural phenotypes, prevents neuronal loss, extends survival rates and delays disease progression in a mouse model of neurodegeneration (Kieran et al., 2004). Similarly, activation of heat-shock responses with geldanamycin inhibits aggregation and prevents cell death (Rimoldi et al., 2001). This suggests that pharmacological activation of the heat-shock response may, therefore, be an effective therapeutic approach to treating neurodegenerative diseases. However, excessive upregulation of chaperones might lead to undesirable side-effects, such as alterations in cell cycle regulation and cancer (Mosser and Morimoto, 2004). Therefore, a delicate balance of chaperones is likely to be required for a beneficial neuroprotective effect. For instance, chemical or molecular chaperones, used in combination with a pharmacological agent that upregulates the synthesis of molecular chaperones, might be a valid therapeutic approach for treating spinocerebellar ataxias caused by polyglutamine expansions. Aggregate formation has also been successfully targeted with inhibitors of transglutaminase, such as cystamine, which reduces apoptotic cell death and alleviates disease symptoms by the expanded polyglutamine (Dedeoglu et al., 2002; Karpuj et al., 2002).
Compounds targeting mitochondrial function such as coenzyme Q10 (Shults, 2003), creatine (Ryu et al., 2005) and taurousodeoxycholic acid (TUDCA) (Keene et al., 2002), or autophagy, such as the mTor inhibitor rapamycin and its various analogous (Ravikumar et al., 2004), have proved effective at reducing cellular toxicity in animal models, and are currently being tested in clinical trials. Caspase activation, which usually precedes neuronal cell death, can be targeted with caspase inhibitors such as zVAD-fmk, CrmA, cystamine, FADD DN and minocycline. These have proved efficient to prevent disease progression, delay onset of symptoms and extend survival rates in several mouse models of neurodegeneration (Ona et al., 1999; Chen et al., 2000; Lesort et al., 2003). Other agents promoting the clearance of mutant proteins in the CNS or Ca2+ signalling blockers, such as specific inhibitors of the NR2B-subunit of N-methyl-D-aspartate glutamate receptors and blockers of metabotropic glutamate receptor mGluR5 and inositol 1,4,5-trisphosphate receptor InsP3R1, may be beneficial for the treatment of some spinocerebellar ataxia subtypes. Delaying protein accumulation and the associated deleterious effects by enhancing degradation of toxic proteins by the ubiquitin-proteasome pathway could also be employed as therapeutic approaches.
The role that some ataxins play in transcription and, more importantly, the suppression of cytotoxic effects mediated by some of their co-transcriptional regulators can be used to modulate the pathological effects of mutant ataxins, opening the path for new therapeutic strategies for treating some of the SCAs. Recent progress in HDAC research has made possible the development of inhibitors of specific HDAC family proteins and these compounds could be effective candidates for treatment of spinocerebellar ataxias (Dokmanovic and Marks, 2005). Neuroprotective strategies addressed at specific bioenergetic defects might hold particular promise in the treatment of spinocerebellar conditions. In vivo neuroprotection exerted by the insulin growth factor IGF-1 through the PP2-regulated PI3K/Akt signalling pathway raises its possible potential to halt cerebellar neurodegeneration (Leinninger and Feldman, 2005).
Gene therapy and stem cell approaches are being considered for treatment of spinocerebellar neurodegenerations. Delivery of proteins or compounds by viral vectors represents one such gene therapeutic approach. Neural cell replacement therapies are based on the idea that neurological function lost during neurodegeneration could be improved by introducing new cells that can form appropriate connections and replace the function of lost neurons. This strategy has proved to be effective in treating neurodegeneration in Parkinson's disease and amyotrophy lateral sclerosis (Svendsen and Langston, 2004). Both mouse and human embryonic stem cells, when cultured in vitro to produce embryoid bodies, are able to differentiate towards a motor neuron lineage (Wichterle et al., 2002). Remarkably, when neurons created in vitro are introduced into an injured chick spinal cord, some stem cell-derived motor neuron extend axons and innervate appropriate targets. Since neurogenesis does occur in the adult nervous system, another approach could be to stimulate endogenous stem cells in the brain or spinal cord to generate new neurons. Studies to understand the molecular determinants and cues to stimulate endogenous stem cells are under way (Gage, 2002). Although promising, we are only starting to learn the potentials and challenges of stem cells, especially for use in neurodegenerative diseases.
|
Concluding remarks |
|---|
|
TopSummaryIntroductionConcluding remarksReferences |
|---|
Here we review common themes occurring in spinocerebellar neurodegenerative conditions. Progressive neurodegeneration in spinocerebellar ataxias is mediated by mutant proteins capable of inducing neuronal damage by interfering with several molecular pathways including protein aggregation and clearance, transcriptional regulation, the ubiquitin-proteasome system, alterations of calcium homeostasis and activation of pro-apoptotic routes among others. These pathways could act independently or, more likely, interact and enhance each other, triggering the accumulation of cellular damage that eventually leads to dysfunction and, ultimately, the demise of neurons through a series of multiple events. This suggests that simultaneous targeting of several pathways might be therapeutically necessary for preventing neurodegeneration and preserving neuronal function. Understanding how dysregulation of these pathways mediates disease progression is leading to the establishment of effective therapeutic strategies in vivo, which may prove beneficial in the treatment of spinocerebellar ataxias.
|
Acknowledgements |
|---|
We are indebted to Nick Wood (Institute of Neurology, Queen Square, London, UK) for his support, helpful comments and suggestions. This work was supported by the Child Health Research Appeal Trust (CHRAT) and the VI Framework Program (FP6) of the European Commission (EUROSCA Integrated Project LHSM-CT-2004-503304). Research at the Institute of Child Health (ICH) benefits from Research and Development funding from the UK National Health System Executive.
|
References |
|---|
|
TopSummaryIntroductionConcluding remarksReferences |
|---|
Abeliovich A, Paylor R, Chen C, Kim JJ, Wehner JM, Tonegawa S. (1993) PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. Cell 75:1263–71.[CrossRef][Web of Science][Medline]
Albrecht M, Golatta M, Wullner U, Lengauer T. (2004) Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem 271:3155–70.[Web of Science][Medline]
Bonini NM. (2002) Chaperoning brain degeneration. Proc Natl Acad Sci USA 99:16407–11.
Buhmann C, Bussopulos A, Oechsner M. (2003) Dopaminergic response in parkinsonian phenotype of Machado-Joseph disease. Mov Disord 18:219–21.[Medline]
Cagnoli C, Mariotti C, Taroni F, Seri M, Brussino A, Michielotto C, et al. (2006) SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2. Brain 129:235–42.
Chai Y, Berke SS, Cohen RE, Paulson HL. (2004) Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J Biol Chem 279:3605–11.
Chan HY, Warrick JM, Gray-Board GL, Paulson HL, Bonini NM. (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9:2811–20.
Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801.[CrossRef][Web of Science][Medline]
Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, et al. (2003a) Missense mutations in the regulatory domain of PKCgamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 72:839–49.[CrossRef][Web of Science][Medline]
Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, et al. (2003b) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457–68.[CrossRef][Web of Science][Medline]
Chou AH, Yeh TH, Kuo YL, Kao YC, Jou MJ, Hsu CY, et al. (2006) Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-x(L). Neurobiol Dis 21:333–45.[Medline]
Chow MK, Ellisdon AM, Cabrita LD, Bottomley SP. (2004) Polyglutamine expansion in ataxin-3 does not affect protein stability: implications for misfolding and disease. J Biol Chem 279:47643–51.
Chung MY, Lu YC, Cheng NC, Soong BW. (2003) A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23. Brain 126:1293–9.
Clark HB, Burright EN, Yunis WS, Larson S, Wilcox C, Hartman B, et al. (1997) Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations. J Neurosci 17:7385–95.
Coates JC. (2003) Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol 13:463–71.[CrossRef][Web of Science][Medline]
Corral J, Genis D, Banchs I, San Nicolas H, Armstrong J, Volpini V. (2005) Giant SCA8 alleles in nine children whose mother has two moderately large ones. Ann Neurol 57:549–53.[CrossRef][Web of Science][Medline]
Craig K, Keers SM, Archibald K, Curtis A, Chinnery PF. (2004) Molecular epidemiology of spinocerebellar ataxia type 6. Ann Neurol 55:752–5.[Medline]
Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY. (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19:148–54.[CrossRef][Web of Science][Medline]
Cummings CJ, Reinstein E, Sun Y, Antalffy B, Jiang Y, Ciechanover A, et al. (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24:879–92.[CrossRef][Web of Science][Medline]
Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT, et al. (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 10:1511–8.
David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, et al. (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 17:65–70.[CrossRef][Web of Science][Medline]
Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, Kowall NW, et al. (2002) Therapeutic effects of cystamine in a murine model of Huntington's disease. J Neurosci 22:8942–50.
Devos D, Schraen-Maschke S, Vuillaume I, Dujardin K, Naze P, Willoteaux C, et al. (2001) Clinical features and genetic analysis of a new form of spinocerebellar ataxia. Neurol 56:234–8.
Dokmanovic M and Marks PA. (2005) Prospects: histone deacetylase inhibitors. J Cell Biochem 96:293–304.[CrossRef][Web of Science][Medline]
Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF, et al. (1996) Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 59:392–9.[Web of Science][Medline]
Gage FH. (2002) Neurogenesis in the adult brain. J Neurosci 22:612–3.
Gardner RJ, Knight MA, Hara K, Tsuji S, Forrest SM, Storey E. (2005) Spinocerebellar ataxia type 15. Cerebellum 4:47–50.[CrossRef][Medline]
Gazulla J, Errea JM, Benavente I, Tordesillas CJ. (2004) Treatment of ataxia in cortical cerebellar atrophy with the GABAergic drug gabapentin. A preliminary study. Eur Neurol 52:7–11.[Medline]
Gilman S, Sima AA, Junck L, Kluin KJ, Koeppe RA, Lohman ME, et al. (1996) Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 39:241–55.[CrossRef][Web of Science][Medline]
Giunti P, Stevanin G, Worth PF, David G, Brice A, Wood NW. (1999) Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation. Am J Hum Genet 64:1594–603.[CrossRef][Web of Science][Medline]
Green H. (1993) Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell 74:955–6.[CrossRef][Web of Science][Medline]
Gunther P, Storch A, Schwarz J, Sabri O, Steinbach P, Wagner A, et al. (2004) Basal ganglia involvement of a patient with SCA 17—a new form of autosomal dominant spinocerebellar ataxia. J Neurol 251:896–7.[Web of Science][Medline]
Gwinn-Hardy K, Singleton A, O'Suilleabhain P, Boss M, Nicholl D, Adam A, et al. (2001) Spinocerebellar ataxia type 3 phenotypically resembling Parkinson disease in a black family. Arch Neurol 58:296–9.
Harding AE. (1993) Clinical features and classification of inherited ataxias. In Harding AE and Deufel T (Eds.). Inherited ataxias (Raven, New York) Vol 61: pp. 1–14.
He W and Parker R. (2000) Functions of Lsm proteins in mRNA degradation and splicing. Curr Opin Cell Biol 12:346–50.[CrossRef][Web of Science][Medline]
Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R, Schugardt N, et al. (2000) Inhibition of Huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. Proc Natl Acad Sci USA 97:6739–44.
Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S, et al. (2002) Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc Natl Acad Sci USA 99:16400–6.
Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C, et al. (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 13:1257–65.
Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, et al. (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci USA 100:2041–6.
Hoffner G and Djian P. (2005) Transglutaminase and diseases of the central nervous system. Front Biosci 10:3078–92.[CrossRef][Medline]
Holmes SE, O'Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C, et al. (1999) Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is associated with SCA12. Nat Genet 23:391–2.[CrossRef][Web of Science][Medline]
Ichise T, Kano M, Hashimoto K, Yanagihara D, Nakao K, Shigemoto R, et al. (2000) mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288:1832–5.
Igarashi S, Koide R, Shimohata T, Yamada M, Hayashi Y, Takano H, et al. (1998) Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet 18:111–7.[CrossRef][Web of Science][Medline]
Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC, et al. (2006) Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 38:184–90.[CrossRef][Web of Science][Medline]
Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, et al. (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 14:285–91.[CrossRef][Web of Science][Medline]
Infante J, Berciano J, Volpini V, Corral J, Polo JM, Pascual J, et al. (2004) Spinocerebellar ataxia type 2 with Levodopa-responsive parkinsonism culminating in motor neuron disease. Mov Disord 19:848–52.[Medline]
Ishikawa K, Toru S, Tsunemi T, Li M, Kobayashi K, Yokota T, et al. (2005) An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains. Am J Hum Genet 77:280–96.[CrossRef][Web of Science][Medline]
Iwata A, Christianson JC, Bucci M, Ellerby LM, Nukina N, Forno LS, et al. (2005) Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci USA 102:13135–40.
Jin Y, Suzuki H, Maegawa S, Endo H, Sugano S, Hashimoto K, et al. (2003) A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG. EMBO J 22:905–12.[CrossRef][Web of Science][Medline]
Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, et al. (2002) Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med 8:143–9.[CrossRef][Web of Science][Medline]
Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221–7.[CrossRef][Web of Science][Medline]
Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. (2002) Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci USA 99:10671–6.
Khan NL, Giunti P, Sweeney MG, Scherfler C, Brien MO, Piccini P, et al. (2005) Parkinsonism and nigrostriatal dysfunction are associated with spinocerebellar ataxia type 6 (SCA6). Mov Disord 20:1115–9.[Medline]
Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L. (2004) Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 10:402–5.[CrossRef][Web of Science][Medline]
Knight MA, Gardner RJ, Bahlo M, Matsuura T, Dixon JA, Forrest SM, et al. (2004) Dominantly inherited ataxia and dysphonia with dentate calcification: spinocerebellar ataxia type 20. Brain 127:1172–81.
Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, et al. (1994) Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet 6:9–13.[CrossRef][Web of Science][Medline]
Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, et al. (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet 21:379–84.[CrossRef][Web of Science][Medline]
Kouzarides T. (2000) Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19:1176–9.[CrossRef][Web of Science][Medline]
La Spada AR, Fu Y, Sopher BL, Libby RT, Wang X, Li LY, et al. (2001) Polyglutamine-expanded ataxin-7 antagonizes crx function and induces cone-rod dystrophy in a mouse model of sca7. Neuron 31:913–27.[CrossRef][Web of Science][Medline]
Leinninger GM and Feldman EL. (2005) Insulin-like growth factors in the treatment of neurological disease. Endocr Dev 9:135–59.[Medline]
Lesort M, Lee M, Tucholski J, Johnson GV. (2003) Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J Biol Chem 278:3825–30.
Li F, Macfarlan T, Pittman RN, Chakravarti D. (2002) Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem 277:45004–12.
Lim J and Lu KP. (2005) Pinning down phosphorylated tau and tauopathies. Biochem Biophys Acta 1739:311–22.[Medline]
Lin X and Ashizawa T. (2005) Recent progress in spinocerebellar ataxia type-10 (SCA10). Cerebellum 4:37–42.[CrossRef][Medline]
Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY. (2000) Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 3:157–63.[CrossRef][Web of Science][Medline]
Lipinski MM and Yuan J. (2004) Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharmacol 4:85–90.[CrossRef][Web of Science][Medline]
Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, et al. (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:864–7.
Mantuano E, Veneziano L, Jodice C, Frontali M. (2003) Spinocerebellar ataxia type 6 and episodic ataxia type2differences and similarities between two allelic disorders. Cytogenet Genome Res 100:147–53.[CrossRef][Medline]
Matilla A and Radrizzani M. (2005) The Anp32 family of proteins containing leucine-rich repeats. Cerebellum 4:7–18.[Medline]
Matilla A, Koshy BT, Cummings CJ, Isobe T, Orr HT, Zoghbi HY. (1997) The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389:974–8.[CrossRef][Medline]
Matilla A, Gorbea C, Einum DD, Townsend JJ, Michalik A, van Broeckhaven C, et al. (2001) Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex. Hum Mol Genet 10:2821–31.
Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K, et al. (2000) Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 26:191–4.[CrossRef][Web of Science][Medline]
Matsuyama Z, Yanagisawa NK, Aoki Y, Black JL III, Lennon VA, Mori Y, et al. (2004) Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell-death-preventing effect of CaV2.1 Ca2+ channel—loss-of-function cellular model of SCA6. Neurobiol Dis 17:198–204.[CrossRef][Medline]
McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, et al. (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9:2197–202.
McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS, Fischbeck KH. (2001) Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci USA 98:15179–84.
Miyoshi Y, Yamada T, Tanimura M, Taniwaki T, Arakawa K, Ohyagi Y, et al. (2001) A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1-24.1. Neurol 57:96–100.
Mizutani A, Wang L, Rajan H, Vig PJ, Alaynick WA, Thaler JP, et al. (2005) Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J 24:3339–51.[CrossRef][Web of Science][Medline]
Mosser DD and Morimoto RI. (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–18.[CrossRef][Web of Science][Medline]
Muchowski PJ and Wacker JL. (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22.[CrossRef][Web of Science][Medline]
Mutsuddi M, Marshall CM, Benzow KA, Koob MD, Rebay I. (2004) The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila. Curr Biol 14:302–8.[CrossRef][Web of Science][Medline]
Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, et al. (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 6:14–18.[CrossRef][Web of Science][Medline]
Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, et al. (2001) SCA17a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10:1441–8.
Nandagopal R and Moorthy SG. (2004) Dramatic levodopa responsiveness of dystonia in a sporadic case of spinocerebellar ataxia type 3. Postgrad Med J 80:363–5.
Newton AC. (2001) Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101:2353–64.[CrossRef][Web of Science][Medline]
Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A. (2005) The solution structure of the Josephin domain of ataxin-3structural determinants for molecular recognition. Proc Natl Acad Sci USA 102:10493–8.
Okazawa H, Rich T, Chang A, Lin X, Waragai M, Kajikawa M, et al. (2002) Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron 34:701–13.[CrossRef][Web of Science][Medline]
Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, et al. (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399:263–7.[CrossRef][Medline]
Orr H, Chung M-Y, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet al, et al. (1993) Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellar ataxia type 1. Nat Genet 4:221–6.[CrossRef][Web of Science][Medline]
Orrenius S, Zhivotovsky B, Nicotera P. (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4:552–65.[CrossRef][Web of Science][Medline]
Park Y, Hong S, Kim SJ, Kang S. (2005) Proteasome function is inhibited by polyglutamine-expanded ataxin-1the SCA1 gene product. Mol Cells 19:23–30.[Web of Science][Medline]
Petersen OH. (2002) Calcium signal compartmentalization. Biol Res 35:177–82.[Web of Science][Medline]
Philips AV, Timchenko LT, Cooper TA. (1998) Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280:737–41.
Pietrobon D. (2002) Calcium channels and channelopathies of the central nervous system. Mol Neurobiol 25:31–50.[CrossRef][Web of Science][Medline]
Pirker W, Back C, Gerschlager W, Laccone F, Alesch F. (2003) Chronic thalamic stimulation in a patient with spinocerebellar ataxia type 2. Mov Disord 18:222–5.[CrossRef][Medline]
Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al. (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14:269–76.[CrossRef][Web of Science][Medline]
Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–95.[CrossRef][Web of Science][Medline]
Rimoldi M, Servadio A, Zimarino V. (2001) Analysis of heat shock transcription factor for suppression of polyglutamine toxicity. Brain Res Bull 56:353–62.[CrossRef][Medline]
Ross CA and Poirier MA. (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:S10–7.[CrossRef][Medline]
Ryu H, Rosas HD, Hersch SM, Ferrante RJ. (2005) The therapeutic role of creatine in Huntington's disease. Pharmacol Ther 108:193–207.[CrossRef][Web of Science][Medline]
Sakahira H, Breuer P, Hayer-Hartl MK, Hartl FU. (2002) Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Natl Acad Sci USA 99:16412–8.
Sanchez I, Mahlke C, Yuan J. (2003) Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421:373–9.[CrossRef][Medline]
Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, et al. (1996) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 14:277–84.[CrossRef][Web of Science][Medline]
Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J, et al. (2002) Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol 51:302–10.[CrossRef][Web of Science][Medline]
Schols L, Peters S, Szymanski S, Kruger R, Lange S, Hardt C, et al. (2000) Extrapyramidal motor signs in degenerative ataxias. Arch Neurol 57:1495–500.
Schrenk K, Kapfhammer JP, Metzger F. (2002) Altered dendritic development of cerebellar Purkinje cells in slice cultures from protein kinase Cgamma-deficient mice. Neuroscience 110:675–89.[CrossRef][Web of Science][Medline]
Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT. (2004) Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet 13:2535–43.
Shibata H, Huynh DP, Pulst SM. (2000) A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet 9:1303–13.
Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, Naruse S, et al. (2000) Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26:29–36.[CrossRef][Web of Science][Medline]
Shintani T and Klionsky DJ. (2004) Autophagy in health and disease: a double-edged sword. Science 306:990–5.
Shults CW. (2003) Coenzyme Q10 in neurodegenerative diseases. Curr Med Chem 10:1917–21.[CrossRef][Web of Science][Medline]
Simon-Sanchez J, Hanson M, Singleton A, Hernandez D, McInerney A, Nussbaum R, et al. (2005) Analysis of SCA-2 and SCA-3 repeats in parkinsonism: evidence of SCA-2 expansion in a family with autosomal dominant Parkinson's disease. Neurosci Lett 382:191–4.[CrossRef][Web of Science][Medline]
Sontag E. (2001) Protein phosphatase 2A: the Trojan Horse of cellular signaling. Cell Signal 13:7–16.[CrossRef][Web of Science][Medline]
Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–43.[CrossRef][Medline]
Stevanin G, Broussolle E, Streichenberger N, Kopp N, Brice A, Durr A. (2005) Spinocerebellar ataxia with sensory neuropathy (SCA25). Cerebellum 4:58–61.[Medline]
Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM. (2004) Caspase activation inhibits proteasome function during apoptosis. Mol Cell 14:81–93.[CrossRef][Web of Science][Medline]
Svendsen CN and Langston JW. (2004) Stem cells for Parkinson disease and ALS: replacement or protection? Nat Med 10:224–5.[CrossRef][Web of Science][Medline]
Swartz BE, Burmeister M, Somers JT, Rottach KG, Bespalova IN, Leigh RJ. (2002) A form of inherited cerebellar ataxia with saccadic intrusions, increased saccadic speed, sensory neuropathy, and myoclonus. Ann NY Acad Sci 956:441–4.[Web of Science][Medline]
Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, et al. (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10:148–54.[CrossRef][Web of Science][Medline]
Tsai CC, Kao HY, Mitzutani A, Banayo E, Rajan H, McKeown M, et al. (2004) Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proc Natl Acad Sci USA 101:4047–52.
Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, et al. (2005) The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell 122:633–44.[CrossRef][Web of Science][Medline]
van de Warrenburg B, Sinke R, Verschuuren-Bemelmans C, Scheffer H, Brunt E, Ippel P, et al. (2002) Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurol 58:702–8.
van de Warrenburg BP, Hendriks H, Durr A, van Zuijlen MC, Stevanin G, Camuzat A, et al. (2005) Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch-French cohort. Ann Neurol 57:505–12.[CrossRef][Web of Science][Medline]
van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I, et al. (2003) A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebral ataxia. Am J Hum Genet 72:191–9.[CrossRef][Web of Science][Medline]
Verbeek DS, Schelhaas JH, Ippel EF, Beemer FA, Pearson PL, Sinke RJ. (2002) Identification of a novel SCA locus (SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21-q21. Hum Genet 111:388–93.[CrossRef][Web of Science][Medline]
Verbeek DS, van de Warrenburg BP, Wesseling P, Pearson PL, Kremer HP, Sinke RJ. (2004) Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3. Brain 127:2551–7.
Vuillaume I, Devos D, Schraen-Maschke S, Dina C, Lemainque A, Vasseur F, et al. (2002) A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1. Ann Neurol 52:666–70.[CrossRef][Web of Science][Medline]
Wang Q, Bardgett ME, Wong M, Wozniak DF, Lou J, McNeil BD, et al. (2002) Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 35:25–38.[CrossRef][Web of Science][Medline]
Wang HL, Yeh TH, Chou AH, Kuo YL, Luo LJ, He CY, et al. (2006) Polyglutamine-expanded ataxin-7 activates mitochondrial apoptotic pathway of cerebellar neurons by upregulating Bax and downregulating Bcl-x(L). Cell Signal 18:541–52.[Medline]
Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JPA, Nolte D, et al. (2006) Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet [Epub ahead of print].
Wichterle H, Lieberam I, Porter JA, Jessell TM. (2002) Directed differentiation of embryonic stem cells into motor neurons. Cell 110:385–97.[CrossRef][Web of Science][Medline]
Worth PF, Giunti P, Gardner-Thorpe C, Dixon PH, Davis MB, Wood NW. (1999) Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3. Am J Hum Genet 65:420–6.[CrossRef][Web of Science][Medline]
Worth PF, Houlden H, Giunti P, Davis MB, Wood NW. (2000) Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. Nat Genet 24:214–5.[CrossRef][Web of Science][Medline]
Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT, et al. (2004) RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 10:816–20.[CrossRef][Web of Science][Medline]
Yabe I, Sasaki H, Yamashita I, Takei A, Tashiro K. (2001) Clinical trial of acetazolamide in SCA6, with assessment using the Ataxia Rating Scale and body stabilometry. Acta Neurol Scand 104:44–7.[CrossRef][Web of Science][Medline]
Yabe I, Sasaki H, Chen DH, Raskind WH, Bird TD, Yamashita I, et al. (2003) Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma. Arch Neurol 60:1749–51.
Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I. (2002) Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Neurobiol Dis 10:88–99.[CrossRef][Web of Science][Medline]
Yu GY, Howell MJ, Roller MJ, Xie TD, Gomez CM. (2005) Spinocerebellar ataxia type 26 maps to chromosome 19p13.3 adjacent to SCA6. Ann Neurol 57:349–54.[CrossRef][Web of Science][Medline]
Zhang S, Xu L, Lee J, Xu T. (2002) Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell 108:45–56.[CrossRef][Web of Science][Medline]
Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE, Roark M, et al. (2005) A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci USA 102:892–7.
Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, et al. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:62–9.[CrossRef][Web of Science][Medline]
Zoghbi HY. (2000) Spinocerebellar ataxias. Neurobiol Dis 7:523–7.[CrossRef][Web of Science][Medline]
Zoghbi HY and Orr HT. (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23:217–47.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. D. Wilkinson DUBs at a glance J. Cell Sci., July 15, 2009; 122(14): 2325 - 2329. [Full Text] [PDF]
|
|
|
|
 |
|
 D Genis, I Ferrer, J Valls Sole, J Corral, V Volpini, H San Nicolas, J Gich, L Ramio-Torrenta, M Ferrandiz, J Puig, et al. A kindred with cerebellar ataxia and thermoanalgesia J. Neurol. Neurosurg. Psychiatry, May 1, 2009; 80(5): 518 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. E. Becker, P. L. Oliver, M. D. Glitsch, G. T. Banks, F. Achilli, A. Hardy, P. M. Nolan, E. M. C. Fisher, and K. E. Davies A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice PNAS, April 21, 2009; 106(16): 6706 - 6711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Andoh, H. Kishi, K. Motoki, K. Nakanishi, Y. Kuraishi, and A. Muraguchi Protective Effect of IL-18 on Kainate- and IL-1{beta}-Induced Cerebellar Ataxia in Mice J. Immunol., February 15, 2008; 180(4): 2322 - 2328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.L. Mandelli, T. De Simone, L. Minati, M.G. Bruzzone, C. Mariotti, R. Fancellu, M. Savoiardo, and M. Grisoli Diffusion Tensor Imaging of Spinocerebellar Ataxias Types 1 and 2 AJNR Am. J. Neuroradiol., November 1, 2007; 28(10): 1996 - 2000. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Goold, M. Hubank, A. Hunt, J. Holton, R. P. Menon, T. Revesz, M. Pandolfo, and A. Matilla-Duenas Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1 Hum. Mol. Genet., September 1, 2007; 16(17): 2122 - 2134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. B. McClatchy, L. Liao, S. K. Park, J. D. Venable, and J. R. Yates Quantification of the synaptosomal proteome of the rat cerebellum during post-natal development Genome Res., September 1, 2007; 17(9): 1378 - 1388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Jaworski, M. Beem-Miller, G. Lluri, and R. Barrantes-Reynolds Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2 Physiol Genomics, January 17, 2007; 28(2): 168 - 178. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||