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Neurotherapeutics : the Journal of the... Oct 2019Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder characterized by progressive neuronal loss in the cerebellum, brainstem, and... (Review)
Review
Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder characterized by progressive neuronal loss in the cerebellum, brainstem, and retina, leading to cerebellar ataxia and blindness as major symptoms. SCA7 is due to the expansion of a CAG triplet repeat that is translated into a polyglutamine tract in ATXN7. Larger SCA7 expansions are associated with earlier onset of symptoms and more severe and rapid disease progression. Here, we summarize the pathological and genetic aspects of SCA7, compile the current knowledge about ATXN7 functions, and then focus on recent advances in understanding the pathogenesis and in developing biomarkers and therapeutic strategies. ATXN7 is a bona fide subunit of the multiprotein SAGA complex, a transcriptional coactivator harboring chromatin remodeling activities, and plays a role in the differentiation of photoreceptors and Purkinje neurons, two highly vulnerable neuronal cell types in SCA7. Polyglutamine expansion in ATXN7 causes its misfolding and intranuclear accumulation, leading to changes in interactions with native partners and/or partners sequestration in insoluble nuclear inclusions. Studies of cellular and animal models of SCA7 have been crucial to unveil pathomechanistic aspects of the disease, including gene deregulation, mitochondrial and metabolic dysfunctions, cell and non-cell autonomous protein toxicity, loss of neuronal identity, and cell death mechanisms. However, a better understanding of the principal molecular mechanisms by which mutant ATXN7 elicits neurotoxicity, and how interconnected pathogenic cascades lead to neurodegeneration is needed for the development of effective therapies. At present, therapeutic strategies using nucleic acid-based molecules to silence mutant ATXN7 gene expression are under development for SCA7.
Topics: Animals; Ataxin-7; Autophagy; Brain; Disease Models, Animal; Drug Delivery Systems; Gene Targeting; Genetic Therapy; Humans; Neurons; Peptides; Spinocerebellar Ataxias
PubMed: 31432449
DOI: 10.1007/s13311-019-00778-5 -
International Journal of Molecular... Apr 2024The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado-Joseph Disease (MJD) or spinocerebellar ataxia 3 (SCA3) is the most... (Review)
Review
The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado-Joseph Disease (MJD) or spinocerebellar ataxia 3 (SCA3) is the most common autosomal dominant form, caused by the expansion of CAG repeats within the ataxin-3 (ATXN3) gene. This mutation results in the expression of an abnormal protein containing long polyglutamine (polyQ) stretches that confers a toxic gain of function and leads to misfolding and aggregation of ATXN3 in neurons. As a result of the neurodegenerative process, SCA3 patients are severely disabled and die prematurely. Several screening approaches, e.g., druggable genome-wide and drug library screenings have been performed, focussing on the reduction in stably overexpressed ATXN3(polyQ) protein and improvement in the resultant toxicity. Transgenic overexpression models of toxic ATXN3, however, missed potential modulators of endogenous ATXN3 regulation. In another approach to identify modifiers of endogenous expression using a CRISPR/Cas9-modified SK-N-SH wild-type cell line with a -- () cassette under the control of the endogenous promotor, four statins were identified as potential activators of expression. We here provide an overview of the high throughput screening approaches yet performed to find compounds or genomic modifiers of ATXN3(polyQ) toxicity in different SCA3 model organisms and cell lines to ameliorate and halt SCA3 progression in patients. Furthermore, the putative role of cholesterol in neurodegenerative diseases (NDDs) in general and SCA3 in particular is discussed.
Topics: Humans; Animals; Machado-Joseph Disease; Translational Research, Biomedical; Spinocerebellar Ataxias; Translational Science, Biomedical; Animals, Genetically Modified
PubMed: 38612794
DOI: 10.3390/ijms25073984 -
Parkinsonism & Related Disorders Apr 2021Cognitive impairment (CI) is reported but is poorly explored in spinocerebellar ataxia 2 (SCA2). This study was undertaken to evaluate and classify cognitive impairment...
INTRODUCTION
Cognitive impairment (CI) is reported but is poorly explored in spinocerebellar ataxia 2 (SCA2). This study was undertaken to evaluate and classify cognitive impairment in patients with SCA2 and to identify their grey matter (GM) correlates.
METHODS
We evaluated the neurocognitive profile of 35 SCA2 and 30 age-, gender- and education-matched healthy controls using tests for attention, executive functions, learning and memory, language and fluency, and visuomotor constructive ability. Patients were classified into SCA2 with and without CI based on normative data from population and healthy controls. Furthermore, patients with CI were sub-classified based on the number of impaired domains into multi-domain CI (≥3 domains; MDCI) and limited domain CI (≤2 domains; LDCI). The underlying GM changes were identified using voxel based morphometry.
RESULTS
The mean age at onset, duration of disease, and ataxia score was 28.7 ± 8.51 years, 66.7 ± 44.1 months, and 16.1 ± 4.9 points, respectively. CI was present in 71.4% of SCA2 subjects (MDCI: 42.7%; LDCI: 28.5%). Patients with CI had significant atrophy of the posterior cerebellum, sensorimotor cortex, and superior frontal gyrus (FWE p-value <0.05). Patients with MDCI had significant GM atrophy of the angular gyrus compared to LDCI (FWE p-value <0.05).
CONCLUSION
Patients with CI had significant GM involvement of the posterior cerebellum and frontal lobe, suggestive of impairment in the cerebello-fronto-cortical circuitry.
Topics: Adult; Atrophy; Cerebellum; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parietal Lobe; Prefrontal Cortex; Spinocerebellar Ataxias; Young Adult
PubMed: 33756405
DOI: 10.1016/j.parkreldis.2021.02.028 -
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 -
Human Genetics Aug 2023Fatty acid elongase ELOVL5 is part of a protein family of multipass transmembrane proteins that reside in the endoplasmic reticulum where they regulate long-chain fatty...
Fatty acid elongase ELOVL5 is part of a protein family of multipass transmembrane proteins that reside in the endoplasmic reticulum where they regulate long-chain fatty acid elongation. A missense variant (c.689G>T p.Gly230Val) in ELOVL5 causes Spinocerebellar Ataxia subtype 38 (SCA38), a neurodegenerative disorder characterized by autosomal dominant inheritance, cerebellar Purkinje cell demise and adult-onset ataxia. Having previously showed aberrant accumulation of p.G230V in the Golgi complex, here we further investigated the pathogenic mechanisms triggered by p.G230V, integrating functional studies with bioinformatic analyses of protein sequence and structure. Biochemical analysis showed that p.G230V enzymatic activity was normal. In contrast, SCA38-derived fibroblasts showed reduced expression of ELOVL5, Golgi complex enlargement and increased proteasomal degradation with respect to controls. By heterologous overexpression, p.G230V was significantly more active than wild-type ELOVL5 in triggering the unfolded protein response and in decreasing viability in mouse cortical neurons. By homology modelling, we generated native and p.G230V protein structures whose superposition revealed a shift in Loop 6 in p.G230V that altered a highly conserved intramolecular disulphide bond. The conformation of this bond, connecting Loop 2 and Loop 6, appears to be elongase-specific. Alteration of this intramolecular interaction was also observed when comparing wild-type ELOVL4 and the p.W246G variant which causes SCA34. We demonstrate by sequence and structure analyses that ELOVL5 p.G230V and ELOVL4 p.W246G are position-equivalent missense variants. We conclude that SCA38 is a conformational disease and propose combined loss of function by mislocalization and gain of toxic function by ER/Golgi stress as early events in SCA38 pathogenesis.
Topics: Animals; Mice; Spinocerebellar Ataxias; Ataxia; Fatty Acid Elongases; Amino Acid Sequence; Mutation
PubMed: 37199746
DOI: 10.1007/s00439-023-02572-y -
Cerebellum (London, England) Apr 2021Autosomal-dominant spinocerebellar ataxias (SCA) are neurodegenerative diseases characterized by progressive ataxia. Here, we report on neurometabolic alterations in...
Autosomal-dominant spinocerebellar ataxias (SCA) are neurodegenerative diseases characterized by progressive ataxia. Here, we report on neurometabolic alterations in spinocerebellar ataxia type 1 (SCA1; SCA-ATXN1) and 14 (SCA14; SCA-PRKCG) assessed by non-invasive H magnetic resonance spectroscopy. Three Tesla H magnetic resonance spectroscopy was performed in 17 SCA14, 14 SCA1 patients, and in 31 healthy volunteers. We assessed metabolites in the cerebellar vermis, right cerebellar hemisphere, pons, prefrontal, and motor cortex. Additionally, clinical characteristics were obtained for each patient to correlate them with metabolites. In SCA14, metabolic changes were restricted to the cerebellar vermis compared with widespread neurochemical alterations in SCA1. In SCA14, total N-acetylaspartate (tNAA) was reduced in the vermis by 34%. In SCA1, tNAA was reduced in the vermis (24%), cerebellar hemisphere (26%), and pons (25%). SCA14 patients showed 24% lower glutamate+glutamine (Glx) and 46% lower γ-aminobutyric acid (GABA) in the vermis, while SCA1 patients showed no alterations in Glx and GABA. SCA1 revealed a decrease of aspartate (Asp) in the vermis (62%) and an elevation in the prefrontal cortex (130%) as well as an elevation of myo-inositol (Ins) in the cerebellar hemisphere (51%) and pons (46%). No changes of Asp and Ins were detected in SCA14. Beyond, glucose (Glc) was increased in the vermis of both SCA14 (155%) and SCA1 (247%). H magnetic resonance spectroscopy revealed differing neurochemical profiles in SCA1 and SCA14 and confirmed metabolic changes that may be indicative for neuronal loss and dysfunctional energy metabolism. Therefore, H magnetic resonance spectroscopy represents a helpful tool for in-vivo tracking of disease-specific pathophysiology.
Topics: Adult; Aged; Brain; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Spinocerebellar Ataxias
PubMed: 33063293
DOI: 10.1007/s12311-020-01201-y -
Cerebellum (London, England) Jun 2024Spinocerebellar ataxias (SCAs) are a heterogenous group of rare neurodegenerative conditions sharing an autosomal dominant pattern of inheritance. More than 40 SCAs have... (Review)
Review
Spinocerebellar ataxias (SCAs) are a heterogenous group of rare neurodegenerative conditions sharing an autosomal dominant pattern of inheritance. More than 40 SCAs have been genetically determined. However, a systematic review of SCA epidemiology in Europe is still missing. Here we performed a narrative review of the literature on the epidemiology of the most common SCAs in Europe. PubMed, Embase, and MEDLINE were searched from inception until 1 April 2023. All English peer-reviewed articles published were considered and then filtered by abstract examination and subsequently by full text reading. A total of 917 original articles were retrieved. According to the inclusion criteria and after reviewing references for useful papers, a total of 35 articles were included in the review. Overall, SCA3 is the most frequent spinocerebellar ataxia in Europe. Its frequency is strikingly higher in Portugal, followed by Germany, France, and Netherlands. None or few cases were described in Italy, Russia, Poland, Serbia, Finland, and Norway. SCA1 and SCA2 globally displayed similar frequencies, and are more prevalent in Italy, United Kingdom, Poland, Serbia, and France.
Topics: Humans; Spinocerebellar Ataxias; Europe; Prevalence
PubMed: 37698771
DOI: 10.1007/s12311-023-01600-x -
Journal of Human Genetics Mar 2023Spinocerebellar ataxia type 31 (SCA31) is one of the most common forms of autosomal-dominant cerebellar ataxia in Japan. SCA31 has a strong founder effect, which is... (Review)
Review
Spinocerebellar ataxia type 31 (SCA31) is one of the most common forms of autosomal-dominant cerebellar ataxia in Japan. SCA31 has a strong founder effect, which is consistent with the fact that this disease is basically absent in other ethnicities. After searching the entire founder region of a 2-megabase (Mb), we finally identified a 2.5 to 3.8 kb-long complex penta-nucleotide repeat containing (TGGAA), (TAGAA), (TAAAA) and (TAAAATAGAA) as the only genetic change segregating SCA31 individuals from normal people. Furthermore, (TGGAA) was isolated as the only repeat explaining the pathogenesis because other repeats were encountered in control Japanese. From the genomic point of view, the complex penta-nucleotide repeat lies in an intronic segment shared by two genes, BEAN1 (brain expressed, associated with Nedd4) and TK2 (thymidine kinase 2) transcribed in mutually opposite directions. While TK2 is ubiquitously expressed, BEAN1 is transcribed only in the brain. Thus, the complex repeat is bi-directionally transcribed exclusively in the brain, as two independent non-coding repeats. Furthermore, the complex repeat containing (UGGAA) was found to form abnormal RNA structures, called RNA foci, in cerebellar Purkinje cell nuclei of SCA31 patients' brains. Subsequent investigation by over-expressing (UGGAA) in Drosophila revealed that the RNA containing (UGGAA) exerts toxicity in a length- and expression level-dependent manner, whereas its toxicity could be dampened by (UGGAA)-binding proteins, TDP-43, FUS and hnRNP A2/B1. It seems rational to formulate a treatment strategy through enhancing the role of RNA-binding proteins against (UGGAA)-toxicity in SCA31.
Topics: Humans; Introns; Spinocerebellar Ataxias; RNA; Nucleotides
PubMed: 36319738
DOI: 10.1038/s10038-022-01091-4 -
BioMed Research International 2015Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease... (Review)
Review
Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease (PD) like phenotype and atypical parkinsonism have been described especially in SCA2, SCA3, and SCA17 with geographic differences in prevalence. SCA2 is the most frequently reported subtype of SCA related to parkinsonism worldwide. Parkinsonism in SCA2 has unique genetic characteristics, such as low number of expansions and interrupted structures, which may explain the sporadic cases with low penetrance. Parkinsonism in SCA17 is more remarkable in Asian populations especially in Korea. In addition, an unclear cutoff of the pathologic range is the key issue in SCA17 related parkinsonism. SCA3 is more common in western cohorts. SCA6 and SCA8 have also been reported with a PD-like phenotype. Herein, we reviewed the epidemiologic, clinical, genetic, and pathologic features of parkinsonism in SCAs.
Topics: Humans; Parkinsonian Disorders; Spinocerebellar Ataxias
PubMed: 25866756
DOI: 10.1155/2015/125273 -
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