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Neurotherapeutics : the Journal of the... Oct 2019Spinocerebellar ataxia type 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP), which functions as a general transcription... (Review)
Review
Spinocerebellar ataxia type 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP), which functions as a general transcription factor. Like other polyQ expansion-mediated diseases, SCA17 is characterized by late-onset and selective neurodegeneration, despite the disease protein being ubiquitously expressed in the body. To date, the pathogenesis of polyQ diseases is not fully understood, and there are no effective treatments for these devastating disorders. The well-characterized function of TBP and typical neurodegeneration in SCA17 give us opportunities to understand how polyQ expansion causes selective neurodegeneration and to develop effective therapeutics. In this review, we discuss the molecular mechanisms behind SCA17, focusing on transcriptional dysregulation as its major cause. Mounting evidence suggests that reversing transcriptional alterations induced by mutant TBP and reducing the expression of mutant TBP are promising strategies to treat SCA17.
Topics: Animals; Brain; Disease Models, Animal; Genetic Therapy; Humans; Spinocerebellar Ataxias; TATA-Box Binding Protein; Transcription, Genetic; Trinucleotide Repeat Expansion
PubMed: 31317427
DOI: 10.1007/s13311-019-00762-z -
Expert Review of Neurotherapeutics Feb 2022Spinocerebellar ataxias (SCA) are a group of rare neurodegenerative diseases that dramatically affect the lives of affected individuals and their families. Despite... (Review)
Review
INTRODUCTION
Spinocerebellar ataxias (SCA) are a group of rare neurodegenerative diseases that dramatically affect the lives of affected individuals and their families. Despite having a clear understanding of SCA's etiology, there are no current symptomatic or neuroprotective treatments approved by the FDA.
AREAS COVERED
Research efforts have greatly expanded the possibilities for potential treatments, including both pharmacological and non-pharmacological interventions. Great attention is also being given to novel therapeutics based in gene therapy, neurostimulation, and molecular targeting. This review article will address the current advances in the treatment of SCA and what potential interventions are on the horizon.
EXPERT OPINION
SCA is a highly complex and multifaceted disease family with the majority of research emphasizing symptomatic pharmacologic therapies. As pre-clinical trials for SCA and clinical trials for other neurodegenerative conditions illuminate the efficacy of disease modifying therapies such as AAV-mediated gene therapy and ASOs, the potential for addressing SCA at the pre-symptomatic stage is increasingly promising.
Topics: Humans; Spinocerebellar Ataxias
PubMed: 35081319
DOI: 10.1080/14737175.2022.2029703 -
Parkinsonism & Related Disorders Dec 2017Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known.
BACKGROUND
Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known.
OBJECTIVES
To study clinical characteristics and ataxia progression in SCAs with and without dystonia.
METHODS
We studied 334 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and compared the clinical characteristics of SCAs with and without dystonia. We repeatedly measured ataxia progression by the Scale for Assessment and Rating of Ataxia every 6 months for 2 years. Regression models were employed to study the association between dystonia and ataxia progression after adjusting for age, sex and pathological CAG repeats. We used logistic regression to analyze the impact of different repeat expansion genes on dystonia in SCAs.
RESULTS
Dystonia was most commonly observed in SCA3, followed by SCA2, SCA1, and SCA6. Dystonia was associated with longer CAG repeats in SCA3. The CAG repeat number in TBP normal alleles appeared to modify the presence of dystonia in SCA1. The presence of dystonia was associated with higher SARA scores in SCA1, 2, and 3. Although relatively rare in SCA6, the presence of dystonia was associated with slower progression of ataxia.
CONCLUSIONS
The presence of dystonia is associated with greater severity of ataxia in SCA1, 2, and 3, but predictive of a slower progression in SCA6. Complex genetic interactions among repeat expansion genes can lead to diverse clinical symptoms and progression in SCAs.
Topics: Adult; Cohort Studies; Disease Progression; Dystonia; Female; Humans; Male; Middle Aged; Spinocerebellar Ataxias
PubMed: 29089256
DOI: 10.1016/j.parkreldis.2017.10.007 -
Tremor and Other Hyperkinetic Movements... 2019The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery,... (Review)
Review
BACKGROUND
The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery, specific features of the SCAs - clinical, laboratorial, and neuroradiological (NR) - can facilitate establishing the diagnosis. The purpose of this study was to review the particular NR abnormalities in the main SCAs.
METHODS
We conducted a literature search on this topic.
RESULTS
The main NR characteristics of brain imaging (magnetic resonance imaging or computerized tomography) in SCAs were: (1) pure cerebellar atrophy; (2) cerebellar atrophy with other findings (e.g., pontine, olivopontocerebellar, spinal, cortical, or subcortical atrophy; "hot cross bun sign", and demyelinating lesions); (3) selective cerebellar atrophy; (4) no cerebellar atrophy.
DISCUSSION
The main NR abnormalities in the commonest SCAs, are not pathognomonic of any specific genotype, but can be helpful in limiting the diagnostic options. We are progressing to a better understanding of the SCAs, not only genetically, but also pathologically; NR is helpful in the challenge of diagnosing the specific genotype of SCA.
Topics: Brain; Humans; Neuroimaging; Spinocerebellar Ataxias
PubMed: 31632837
DOI: 10.7916/tohm.v0.682 -
Cellular and Molecular Life Sciences :... Oct 2020The family of hereditary cerebellar ataxias is a large group of disorders with heterogenous clinical manifestations and genetic etiologies. Among these, over 30... (Review)
Review
The family of hereditary cerebellar ataxias is a large group of disorders with heterogenous clinical manifestations and genetic etiologies. Among these, over 30 autosomal dominantly inherited subtypes have been identified, collectively referred to as the spinocerebellar ataxias (SCAs). Generally, the SCAs are characterized by a progressive gait impairment with classical cerebellar features, and in a subset of SCAs, accompanied by extra-cerebellar features. Beyond the common gait impairment and cerebellar atrophy, the wide range of additional clinical features observed across the SCAs is likely explained by the diverse set of mutated genes that encode proteins with seemingly disparate functional roles in nervous system biology. By synthesizing knowledge obtained from studies of the various SCAs over the past several decades, convergence onto a few key cellular changes, namely ion channel dysfunction and transcriptional dysregulation, has become apparent and may represent central mechanisms of cerebellar disease pathogenesis. This review will detail our current understanding of the molecular pathogenesis of the SCAs, focusing primarily on the first described autosomal dominant spinocerebellar ataxia, SCA1, as well as the emerging common core mechanisms across the various SCAs.
Topics: Animals; Cerebellum; Humans; Nuclear Proteins; Spinocerebellar Ataxias; Spinocerebellar Degenerations
PubMed: 32306062
DOI: 10.1007/s00018-020-03520-z -
Movement Disorders : Official Journal... Oct 2021Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular,...
BACKGROUND
Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity.
OBJECTIVE
The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease.
METHODS
We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels.
RESULTS
The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume.
CONCLUSION
Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Brain; Cerebellum; Humans; Machado-Joseph Disease; Spinocerebellar Ataxias
PubMed: 33951232
DOI: 10.1002/mds.28610 -
Arquivos de Neuro-psiquiatria Dec 2009Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of neurodegenerative diseases characterized by progressive cerebellar ataxia in association with some or... (Review)
Review
UNLABELLED
Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of neurodegenerative diseases characterized by progressive cerebellar ataxia in association with some or all of the following conditions: ophthalmoplegia, pyramidal signs, movement disorders, pigmentary retinopathy, peripheral neuropathy, cognitive dysfunction and dementia.
OBJECTIVE
To carry out a clinical and genetic review of the main types of SCA.
METHOD
The review was based on a search of the PUBMED and OMIM databases.
RESULTS
Thirty types of SCAs are currently known, and 16 genes associated with the disease have been identified. The most common types are SCA type 3, or Machado-Joseph disease, SCA type 10 and SCA types 7, 2, 1 and 6. SCAs are genotypically and phenotypically very heterogeneous. A clinical algorithm can be used to distinguish between the different types of SCAs.
CONCLUSIONS
Detailed clinical neurological examination of SCA patients can be of great help when assessing them, and the information thus gained can be used in an algorithm to screen patients before molecular tests to investigate the correct etiology of the disease are requested.
Topics: Humans; Spinocerebellar Ataxias
PubMed: 20069236
DOI: No ID Found -
Neurotherapeutics : the Journal of the... Apr 2019Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs... (Review)
Review
Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.
Topics: Humans; Peptides; Spinocerebellar Ataxias; Trinucleotide Repeat Expansion
PubMed: 30607747
DOI: 10.1007/s13311-018-00696-y -
Journal of Clinical Neuroscience :... Jun 2021Coronavirus disease 2019 (COVID-19) is currently a global concern, and the psychological impact cannot be overlooked. Our purpose was to evaluate the anxiety and...
Coronavirus disease 2019 (COVID-19) is currently a global concern, and the psychological impact cannot be overlooked. Our purpose was to evaluate the anxiety and depression in spinocerebellar ataxia (SCA) patients during the pandemic and to analyse the influencing factors. We conducted an online questionnaire survey among 307 SCA patients from China and selected 319 healthy people matched by sex and age as the control group. The questionnaire included general information, the self-rating anxiety scale (SAS), and the self-rating depression scale (SDS). The relevant factors included COVID-19 risk factors, age, sex, body mass index (BMI), educational background, disease course, score on the scale for the assessment and rating of ataxia (SARA), Mini-mental State Examination (MMSE) and International Cooperative Ataxia Rating Scale (ICARS). The proportion of SCA patients with anxiety was 34.9%, and the proportion with depression was 56.7%. The SAS and SDS scores of the SCA patients were significantly higher than those of the control group (SAS: 45.8 ± 10.1 vs. 40.6 ± 8.9, P < 0.01; SDS: 55.1 ± 12.2 vs. 43.6 ± 11.9, P < 0.01). In SCA3, the risk of exposure to COVID-19, educational level, disease course and the severity of ataxia may be factors affecting patients' mental health. More attention should be paid to the mental health of SCA patients during the COVID-19 pandemic.
Topics: Adult; Age Factors; Aged; Anxiety; Body Mass Index; COVID-19; China; Cross-Sectional Studies; Depression; Educational Status; Female; Humans; Male; Mental Health; Mental Status and Dementia Tests; Middle Aged; Pandemics; Risk Factors; Self Report; Sex Factors; Spinocerebellar Ataxias; Surveys and Questionnaires; Young Adult
PubMed: 33992201
DOI: 10.1016/j.jocn.2021.03.004 -
Neurotherapeutics : the Journal of the... Oct 2019Spinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This... (Review)
Review
Spinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This disease is caused by a 2.5- to 3.8-kb-long complex pentanucleotide repeat containing (TGGAA), (TAGAA), (TAAAA), and (TAAAATAGAA) in an intron of the gene called BEAN1 (brain expressed, associated with Nedd4). By comparing various pentanucleotide repeats in this particular locus among control Japanese and Caucasian populations, it was found that (TGGAA) was the only sequence segregating with SCA31, strongly suggesting the pathogenicity of (TGGAA). The complex repeat also lies in an intron of another gene, TK2 (thymidine kinase 2), which is transcribed in the opposite direction, indicating that the complex repeat is bi-directionally transcribed as noncoding repeats. In SCA31 human brains, (UGGAA), the BEAN1 transcript of SCA31 mutation was found to form abnormal RNA structures called RNA foci in cerebellar Purkinje cell nuclei. Subsequent RNA pulldown analysis disclosed that (UGGAA) binds to RNA-binding proteins TDP-43, FUS, and hnRNP A2/B1. In fact, TDP-43 was found to co-localize with RNA foci in human SCA31 Purkinje cells. To dissect the pathogenesis of (UGGAA) in SCA31, we generated transgenic fly models of SCA31 by overexpressing SCA31 complex pentanucleotide repeats in Drosophila. We found that the toxicity of (UGGAA) is length- and expression level-dependent, and it was dampened by co-expressing TDP-43, FUS, and hnRNP A2/B1. Further investigation revealed that TDP-43 ameliorates (UGGAA) toxicity by directly fixing the abnormal structure of (UGGAA). This led us to propose that TDP-43 acts as an RNA chaperone against toxic (UGGAA). Further research on the role of RNA-binding proteins as RNA chaperones may provide a novel therapeutic strategy for SCA31.
Topics: Animals; Base Sequence; Disease Models, Animal; Forecasting; Humans; Microsatellite Repeats; Mutation; Purkinje Cells; Spinocerebellar Ataxias
PubMed: 31755042
DOI: 10.1007/s13311-019-00804-6