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Journal of Neurology Feb 2019Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative ataxic disorders with autosomal dominant inheritance. We aim to provide an update on the... (Review)
Review
Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative ataxic disorders with autosomal dominant inheritance. We aim to provide an update on the recent clinical and scientific progresses in SCA where numerous novel genes have been identified with next-generation sequencing techniques. The main disease mechanisms of these SCAs include toxic RNA gain-of-function, mitochondrial dysfunction, channelopathies, autophagy and transcription dysregulation. Recent studies have also demonstrated the importance of DNA repair pathways in modifying SCA with CAG expansions. In addition, we summarise the latest technological advances in detecting known and novel repeat expansion in SCA. Finally, we discuss the roles of antisense oligonucleotides and RNA-based therapy as potential treatments.
Topics: Humans; Spinocerebellar Ataxias
PubMed: 30284037
DOI: 10.1007/s00415-018-9076-4 -
Neuron Aug 2023Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using...
Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1.
Topics: Mice; Humans; Animals; Purkinje Cells; Parvalbumins; Proteomics; Mice, Transgenic; Spinocerebellar Ataxias; Cerebellum; Interneurons; Nerve Degeneration; Disease Models, Animal; Ataxin-1; Membrane Proteins; Nerve Tissue Proteins
PubMed: 37321222
DOI: 10.1016/j.neuron.2023.05.016 -
Brain : a Journal of Neurology Jun 2023Polyglutamine diseases are a group of neurodegenerative disorders caused by an abnormal expansion of CAG repeat tracts in the codifying regions of nine, otherwise...
Polyglutamine diseases are a group of neurodegenerative disorders caused by an abnormal expansion of CAG repeat tracts in the codifying regions of nine, otherwise unrelated, genes. While the protein products of these genes are suggested to play diverse cellular roles, the pathogenic mutant proteins bearing an expanded polyglutamine sequence share a tendency to self-assemble, aggregate and engage in abnormal molecular interactions. Understanding the shared paths that link polyglutamine protein expansion to the nervous system dysfunction and the degeneration that takes place in these disorders is instrumental to the identification of targets for therapeutic intervention. Among polyglutamine diseases, spinocerebellar ataxias (SCAs) share many common aspects, including the fact that they involve dysfunction of the cerebellum, resulting in ataxia. Our work aimed at exploring a putative new therapeutic target for the two forms of SCA with higher worldwide prevalence, SCA type 2 (SCA2) and type 3 (SCA3), which are caused by expanded forms of ataxin-2 (ATXN2) and ataxin-3 (ATXN3), respectively. The pathophysiology of polyglutamine diseases has been described to involve an inability to properly respond to cell stress. We evaluated the ability of GTPase-activating protein-binding protein 1 (G3BP1), an RNA-binding protein involved in RNA metabolism regulation and stress responses, to counteract SCA2 and SCA3 pathology, using both in vitro and in vivo disease models. Our results indicate that G3BP1 overexpression in cell models leads to a reduction of ATXN2 and ATXN3 aggregation, associated with a decrease in protein expression. This protective effect of G3BP1 against polyglutamine protein aggregation was reinforced by the fact that silencing G3bp1 in the mouse brain increases human expanded ATXN2 and ATXN3 aggregation. Moreover, a decrease of G3BP1 levels was detected in cells derived from patients with SCA2 and SCA3, suggesting that G3BP1 function is compromised in the context of these diseases. In lentiviral mouse models of SCA2 and SCA3, G3BP1 overexpression not only decreased protein aggregation but also contributed to the preservation of neuronal cells. Finally, in an SCA3 transgenic mouse model with a severe ataxic phenotype, G3BP1 lentiviral delivery to the cerebellum led to amelioration of several motor behavioural deficits. Overall, our results indicate that a decrease in G3BP1 levels may be a contributing factor to SCA2 and SCA3 pathophysiology, and that administration of this protein through viral vector-mediated delivery may constitute a putative approach to therapy for these diseases, and possibly other polyglutamine disorders.
Topics: Humans; Mice; Animals; DNA Helicases; Heat-Shock Proteins; Protein Aggregates; Stress Granules; Poly-ADP-Ribose Binding Proteins; RNA Helicases; RNA Recognition Motif Proteins; Spinocerebellar Ataxias; Ataxin-3; Mice, Transgenic; Machado-Joseph Disease
PubMed: 36511898
DOI: 10.1093/brain/awac473 -
Biochimica Et Biophysica Acta.... Nov 2018Spinocerebellar ataxia (SCA) is a neural disorder, which is caused by degenerative changes in the cerebellum. SCA is primarily characterized by gait ataxia, and... (Review)
Review
Spinocerebellar ataxia (SCA) is a neural disorder, which is caused by degenerative changes in the cerebellum. SCA is primarily characterized by gait ataxia, and additional clinical features include nystagmus, dysarthria, tremors and cerebellar atrophy. Forty-four hereditary SCAs have been identified to date, along with >35 SCA-associated genes. Despite the great diversity and distinct functionalities of the SCA-related genes, accumulating evidence supports the occurrence of a common pathophysiological event among several hereditary SCAs. Altered calcium (Ca) homeostasis in the Purkinje cells (PCs) of the cerebellum has been proposed as a possible pathological SCA trigger. In support of this, signaling events that are initiated from or lead to aberrant Ca release from the type 1 inositol 1,4,5-trisphosphate receptor (IPR1), which is highly expressed in cerebellar PCs, seem to be closely associated with the pathogenesis of several SCA types. In this review, we summarize the current research on pathological hereditary SCA events, which involve altered Ca homeostasis in PCs, through IPR1 signaling.
Topics: Animals; Calcium; Calcium Signaling; Cerebellum; Disease Susceptibility; Endoplasmic Reticulum; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Inositol 1,4,5-Trisphosphate Receptors; Mutation; Purkinje Cells; Spinocerebellar Ataxias
PubMed: 29777722
DOI: 10.1016/j.bbamcr.2018.05.009 -
Journal of the Neurological Sciences Dec 2022The spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders with an autosomal dominant inheritance. Symptoms include poor coordination and... (Review)
Review
The spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders with an autosomal dominant inheritance. Symptoms include poor coordination and balance, peripheral neuropathy, impaired vision, incontinence, respiratory insufficiency, dysphagia, and dysarthria. Although many patients with SCA have respiratory-related complications, the exact mechanism and extent of this pathology remain unclear. This review aims to provide an update on the recent clinical and preclinical scientific findings on neuropathology causing respiratory insufficiency in SCA.
Topics: Humans; Neurology; Spinocerebellar Ataxias; Respiratory Insufficiency; Dysarthria; Deglutition Disorders
PubMed: 36410186
DOI: 10.1016/j.jns.2022.120493 -
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 -
Biomolecules May 2023Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an... (Review)
Review
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the gene and is characterized mostly by a profound loss of cerebellar Purkinje cells, leading to disturbances in coordination, balance, and gait. At present, no curative treatment is available for SCA1. However, increasing knowledge on the cellular and molecular mechanisms of SCA1 has led the way towards several therapeutic strategies that can potentially slow disease progression. SCA1 therapeutics can be classified as genetic, pharmacological, and cell replacement therapies. These different therapeutic strategies target either the (mutant) RNA or the ataxin-1 protein, pathways that play an important role in downstream SCA1 disease mechanisms or which help restore cells that are lost due to SCA1 pathology. In this review, we will provide a summary of the different therapeutic strategies that are currently being investigated for SCA1.
Topics: Humans; Cerebellum; Spinocerebellar Ataxias; Ataxin-1; Purkinje Cells
PubMed: 37238658
DOI: 10.3390/biom13050788 -
Brain : a Journal of Neurology Nov 2018
Topics: Exome; Genetic Predisposition to Disease; Humans; Spinocerebellar Ataxias
PubMed: 30312375
DOI: 10.1093/brain/awy258 -
Journal of Neuroscience Research Aug 2017Spinocerebellar ataxia type 17 (SCA17) is a type of autosomal dominant cerebellar ataxia (ADCA) characterized by variable manifestations, including cerebellar ataxia,... (Review)
Review
Spinocerebellar ataxia type 17 (SCA17) is a type of autosomal dominant cerebellar ataxia (ADCA) characterized by variable manifestations, including cerebellar ataxia, dementia, and psychiatric symptoms. Since the identification of a CAG repeat expansion in the TATA-box binding protein (TBP) gene in a patient with ataxia in 1999 and then verification of this expansion in patients with SCA17 in 2001, several SCA17 rodent models, including both knock-in and transgenic models in mice and rats, have been established to explore the phenotypic features and pathogenesis of SCA17. These animal models revealed different pathological changes and phenotypes that are associated with the expression of mutant TBP protein and the CAG repeat lengths. It is important to understand how mutant TBP can cause differential pathological events in SCA17 animal models. In this review, we summarize and compare these animal models for the nature of transgenes and their expression as well as phenotypical features. We also discuss potential directions for future studies. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Animals, Genetically Modified; Disease Models, Animal; Phenotype; Rodentia; Spinocerebellar Ataxias; TATA-Box Binding Protein; Trinucleotide Repeats
PubMed: 27859490
DOI: 10.1002/jnr.23984 -
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