The Ever Expanding Spinocerebellar Ataxias. Editorial

The spinocerebellar ataxias (SCAs) are a clinically, genetically, and neuropathologically heterogeneous group of neurological disorders defined by variable degrees of cerebellar ataxia often accompanied by additional cerebellar and non-cerebellar symptoms that, in many cases, defy differentiation based on clinical characterisation alone. The clinical symptoms are triggered by neurodegeneration of the cerebellum and its relay connexions. The current identification of at least 43 SCA subtypes and the causative molecular defects in 27 of them refine the clinical diagnosis, provide molecular testing of at risk, a/pre-symptomatic, prenatal or pre-implantation and facilitate genetic counselling. The recent discovery of new causative SCA genes along with the respective scientific advances is uncovering high complexity and altered molecular pathways involved in the mechanisms by which the mutant gene products cause pathogenesis. Fortunately, the intensive ongoing clinical and neurogenetic research together with the applied molecular approaches is sure to yield scientific advances that will be translated into developing effective treatments for the spinocerebellar ataxias and other similar neurological conditions.     

Spinocerebellar ataxias caused by polyglutamine expansions: A review of therapeutic strategies

Six of the spinocerebellar ataxias (SCAs) are caused by expanded CAG trinucleotide repeats encoding polyglutamine tracts in different genes. Together with three other neurodegenerative diseases they represent the polyglutamine repeat disorders. These disorders share many pathological features beyond a common genetic mechanism. They are the subject of considerable research efforts to elucidate their basic pathophysiologies, with the hope of using this knowledge to develop disease modifying treatments. Here we examine the biology that underpins possible therapeutic strategies for the SCAs caused by CAG repeats and review supportive data from cell and animal models. Therapeutic strategies include silencing gene expression, increasing protein clearance, reducing the toxicity of the protein, influencing downstream pathways activated by the mutant protein and transplantation. We also consider strategies which have been tested in other polyglutamine diseases that may generalize to these SCAs. Finally, we review clinical trials and consider the problems of translating the increasing amount of promising laboratory data into human trials.     

Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3

To date, nearly 30 distinct genetic forms of dominantly inherited ataxia are known to exist. Of these, Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is perhaps the most common in many regions of the world including the United States. This article discusses MJD/SCA3 as a paradigm example of the dominant ataxias, which are collectively known as the spinocerebellar ataxias. Using MJD/SCA3 as a starting point, the article reviews common clinical and genetic features of the SCAs and highlights new insights into molecular mechanisms, especially of the SCAs caused by polyglutamine expansion. Also discussed are current and future therapeutic opportunities for MJD/SCA3 in particular, many of which have relevance to other SCAs.     

Deranged Calcium Signaling in Purkinje Cells and Pathogenesis in Spinocerebellar Ataxia 2 (SCA2) and Other Ataxias

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 30 autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by progressive ataxia and cerebellar atrophy. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, 17 different gene loci have so far been implicated as culprits in these SCAs. It is not currently understood how mutations in these 17 proteins lead to the cerebellar atrophy and ataxia. Several pathogenic mechanisms have been studied in SCAs but there is yet to be a promising target for successful treatment of SCAs. Emerging research suggests that a fundamental cellular signaling pathway is disrupted by a majority of these mutated genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. We propose that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic sympoms and eventually proceed to Purkinje cell death. Here, we discuss a calcium hypothesis of Purkinje cell neurodegeneration in SCAs by primarily focusing on an example of spinocerebellar ataxia 2 (SCA2). We will also present evidence linking deranged calcium signaling to the pathogenesis of other SCAs (SCA1, 3, 5, 6, 14, 15/16) that lead to significant Purkinje cell dysfunction and loss in patients.     

From fruit fly to bedside: translating lessons from Drosophila models of neurodegenerative disease

PURPOSE OF REVIEW: Fly models have been developed for a variety of neurodegenerative disorders, and the field is beginning to harness the power of Drosophila genetics to dissect pathways of disease pathogenesis and identify targets for therapeutic intervention. In this review, we emphasize the most recent accomplishments and chart the potential rewards in translating lessons from Drosophila models to clinical therapeutics. RECENT FINDINGS: The conservation of human disease genes in the Drosophila genome forms the basis for several recent investigations of the normal biological functions of genes implicated in neurodegenerative disease. In addition, transgenic approaches continue to expand the list of diseases modeled in Drosophila that now includes Parkinson's disease, Alzheimer's disease, Huntington's disease, and several spinocerebellar ataxias. Studies based on these models suggest that protein folding and degradation pathways play an important role in Parkinson's disease and the polyglutamine repeat disorders, and that kinases and apoptotic pathways may modulate neurodegeneration in tauopathies. SUMMARY: Ongoing genetic studies with Drosophila neurodegenerative disease models promise to enhance our understanding of disease pathogenesis and generate target lists for future investigational research and drug development. The next challenge will be distilling a growing number of possible targets into a shortlist for fast-track drug design and clinical trials. With the advent of neurodegenerative disease models, the fruit fly is rapidly assuming a unique niche in bench to bedside research.     

Spinocerebellar ataxias: an update

PURPOSE OF REVIEW: Here we discuss recent advances regarding the molecular genetic basis of dominantly inherited ataxias. RECENT FINDINGS: Important recent observations include insights into the mechanisms by which expanded polyglutamine causes cerebellar degeneration; new findings regarding how noncoding expansions may cause disease; the discovery that conventional (i.e. nonrepeat) mutations underlie recently identified ataxias; and growing recognition that multiple biological pathways, when perturbed, can cause cerebellar degeneration. SUMMARY: The dominant ataxias, also known as spinocerebellar ataxias, continue to grow in number. Here we review the major categories of spinocerebellar ataxias: expanded polyglutamine ataxias; noncoding repeat ataxias; and ataxias caused by conventional mutations. After discussing features shared by these disorders, we present recent evidence supporting a toxic protein mechanism for the polyglutamine spinocerebellar ataxias and the recognition that both protein misfolding and perturbations in nuclear events represent key events in pathogenesis. Less is known about pathogenic mechanisms in spinocerebellar ataxias due to noncoding repeats, though a toxic RNA effect remains possible. Newly discovered, conventional mutations in spinocerebellar ataxias suggest a wide range of biological pathways can be disrupted to cause progressive ataxia. Finally, we discuss how new mechanistic insights can drive the push toward preventive treatment.     

Milestones in ataxia

The past 25 years have seen enormous progress in the deciphering of the genetic and molecular basis of ataxias, resulting in improved understanding of their pathogenesis. The most significant milestones during this period were the cloning of the genes associated with the common spinocerebellar ataxias, ataxia telangiectasia, and Friedreich ataxia. To date, the causative mutations of more than 30 spinocerebellar ataxias and 20 recessive ataxias have been identified. In addition, there are numerous acquired ataxias with defined molecular causes, so that the entire number of distinct ataxia disorders exceeds 50 and possibly approaches 100. Despite this enormous heterogeneity, a few recurrent pathophysiological themes stand out. These include protein aggregation, failure of protein homeostasis, perturbations in ion channel function, defects in DNA repair, and mitochondrial dysfunction. The clinical phenotypes of the most common ataxia disorders have been firmly established, and their natural history is being studied in ongoing large observational trials. Effective therapies for ataxias are still lacking. However, novel drug targets are under investigation, and it is expected that there will be an increasing number of therapeutic trials in ataxia. © 2011 Movement Disorder Society     

Cognitive impairment in SCA-19

The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders characterised by progressive cerebellar dysfunction in combination with various associated features. Since 1993, ADCAs have been increasingly characterised in terms of their genetic mutation and are currently referred to as spinocerebellar ataxias (SCAs). The discovery of genetic abnormalities offers the opportunity to study the possible interaction between the identified gene mutation and cognitive function. In this study, we focus on the neuropsychological abnormalities in a Dutch ADCA family, in which a new locus was recently identified (SCA-19). The family members showed frontal-executive dysfunction, with global cognitive impairment occurring in some of the more severely affected patients. Interestingly, the neuropsychological profile of this new family seems to overlap that of individuals with various other SCAs. Apparently, similar pattern of neuronal degeneration in various SCA subtypes accounts for the neuropsychological dysfunction, which is thus not genotype specific.     

Transcriptional malfunctioning of heat shock protein gene expression in spinocerebellar ataxias

Among the various dominantly-inherited spinocerebellar ataxias (SCAs), at least seven of them belong to the polyglutamine disease group and are caused by glutamine-coding CAG triplet repeat expansion. The expanded coding CAG repeat translates into a polyglutamine stretch in the disease protein, which leads to late-onset and progressive neurodegeneration. Expanded polyglutamine adopts a misfolded protein conformation, and is itself a cellular stressor which induces robust heat shock response (HSR). Under polyglutamine stress, heat shock proteins (Hsps) are produced in neurons to assist refolding and/or promote the degradation of misfolded proteins. Along with the progressive nature of polyglutamine degeneration, a gradual decline of HSR in degenerating neurons was observed. Such kind of reduction can be observed in a large family of hsp gene expression, including hsp22, 26, 27, and 70. This underscores an intimate relationship between the inducibility of hsp gene expression and the disease progression. In this review, we describe the current understandings of hsp gene dysregulation in polyglutamine disease.     

Multiple system atrophy in a patient with the spinocerebellar ataxia 3 gene mutation.

The cerebellar variant of multiple system atrophy (MSA-C) has overlapping clinical features with the hereditary spinocerebellar ataxias (SCAs), but can usually be distinguished on a clinical basis. We describe a patient who developed a sporadic, late-onset, rapidly progressive neurodegenerative disorder consistent with MSA-C. Genetic testing, however, showed an abnormal expansion of one allele of the spinocerebellar ataxia 3 (SCA3) gene. The clinical impression of MSA-C was confirmed by identification of numerous alpha-synuclein-containing glial cytoplasmic inclusions on autopsy. These findings suggest that abnormal expansion of the SCA3 gene may be a risk factor for the development of MSA-C.     

Dilemma of multiple system atrophy and spinocerebellar ataxias

Multiple system atrophy (MSA) and spinocerebellar ataxias (SCAs) are both progressive neurodegenerative disorders, which can manifest cerebellar dysfunctions and parkinsonism-related symptoms, although the former is sporadic and the latter is autosomal dominant disease. Routinely, diagnosis is primarily based on clinical information—thorough history and physical examination should be included. Provided family history obtained, distinguishing SCAs from MSA is easy. However, how can we diagnose MSA or SCAs, in case of insufficient and unconvinced clinical symptoms or family history? Especially, familial MSA cases had been reported recently. We may drop into a dilemma resulting from analogous manifestations between MSA and SCAs. Herein, we aim to give a comprehensive introduction of MSA and SCAs, mainly in phenotype and genotype, and then address the connection and difference between them. Recently, some studies had been put forward to figure out the overlapped features between MSA and SCAs. Through this review, we want to discuss the possibility of misdiagnosis between MSA and SCAs.     

Other causes of ataxia in patients with SCA mutations

Autosomal dominant spinocerebellar ataxias (SCAs) are slowly progressive and have a variable clinical presentation. Overlapping clinical features among the SCAs make the clinical diagnosis of these ataxias difficult. Even when genetic testing identifies an SCA mutation, clinicians should be vigilant for other causes of neurological dysfunction in these patients. We report two patients who developed other causes of ataxia in the setting of SCA-3 and SCA-8 mutations, respectively.