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Journal of Neurology Jan 2023This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis... (Review)
Review
This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and recent therapeutic developments. Initial approach facing a patient with cerebellar ataxia requires family medical history, physical examination, exclusions of acquired causes and genetic analysis, including Next-Generation Sequencing (NGS). To guide diagnosis, several algorithms and a new genetic nomenclature for recessive cerebellar ataxias have been proposed. The challenge of NGS analysis is the identification of causative variant, trio analysis being usually the most appropriate option. Public genomic databases as well as pathogenicity prediction software facilitate the interpretation of NGS results. We also report on key clinical points for the diagnosis of the main ICAs, including Friedreich ataxia, CANVAS, polyglutamine spinocerebellar ataxias, Fragile X-associated tremor/ataxia syndrome. Rarer forms should not be neglected because of diagnostic biomarkers availability, disease-modifying treatments, or associated susceptibility to malignancy. Diagnostic difficulties arise from allelic and phenotypic heterogeneity as well as from the possibility for one gene to be associated with both dominant and recessive inheritance. To complicate the phenotype, cerebellar cognitive affective syndrome can be associated with some subtypes of cerebellar ataxia. Lastly, we describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.
Topics: Humans; Cerebellar Ataxia; Friedreich Ataxia; Mutation; Ataxia; Spinocerebellar Ataxias
PubMed: 36152050
DOI: 10.1007/s00415-022-11383-6 -
Neurobiology of Disease Feb 2020Tandem repeat diseases include the neurodegenerative disorders known as polyglutamine (polyQ) diseases, caused by CAG repeat expansions in the coding regions of the... (Review)
Review
Tandem repeat diseases include the neurodegenerative disorders known as polyglutamine (polyQ) diseases, caused by CAG repeat expansions in the coding regions of the respective disease genes. The nine known polyQ disease include Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and six spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17). The underlying disease mechanism in the polyQ diseases is thought principally to reflect dominant toxic properties of the disease proteins which, when harboring a polyQ expansion, differentially interact with protein partners and are prone to aggregate. Among the polyQ diseases, SCA3 is the most common SCA, and second to HD in prevalence worldwide. Here we summarize current understanding of SCA3 disease mechanisms within the broader context of the broader polyQ disease field. We emphasize properties of the disease protein, ATXN3, and new discoveries regarding three potential pathogenic mechanisms: 1) altered protein homeostasis; 2) DNA damage and dysfunctional DNA repair; and 3) nonneuronal contributions to disease. We conclude with an overview of the therapeutic implications of recent mechanistic insights.
Topics: Animals; Humans; Machado-Joseph Disease; Peptides; Trinucleotide Repeat Expansion
PubMed: 31669734
DOI: 10.1016/j.nbd.2019.104635 -
Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2.Cell Reports Oct 2022Mutations in the ataxin-2 gene (ATXN2) cause the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). A therapeutic...
Mutations in the ataxin-2 gene (ATXN2) cause the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). A therapeutic strategy using antisense oligonucleotides targeting ATXN2 has entered clinical trial in humans. Additional ways to decrease ataxin-2 levels could lead to cheaper or less invasive therapies and elucidate how ataxin-2 is normally regulated. Here, we perform a genome-wide fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in human cells and identify genes encoding components of the lysosomal vacuolar ATPase (v-ATPase) as modifiers of endogenous ataxin-2 protein levels. Multiple FDA-approved small molecule v-ATPase inhibitors lower ataxin-2 protein levels in mouse and human neurons, and oral administration of at least one of these drugs-etidronate-is sufficient to decrease ataxin-2 in the brains of mice. Together, we propose v-ATPase as a drug target for ALS and SCA2 and demonstrate the value of FACS-based screens in identifying genetic-and potentially druggable-modifiers of human disease proteins.
Topics: Animals; Humans; Mice; Ataxin-2; Amyotrophic Lateral Sclerosis; Vacuolar Proton-Translocating ATPases; Pharmaceutical Preparations; Etidronic Acid; Spinocerebellar Ataxias; Oligonucleotides, Antisense
PubMed: 36288714
DOI: 10.1016/j.celrep.2022.111508 -
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 -
European Journal of Paediatric... Jul 2021CACNA1A pathogenic mutations are involved in various neurological phenotypes including episodic ataxia (EA2), spinocerebellar ataxia (SCA6), and familial hemiplegic...
CACNA1A pathogenic mutations are involved in various neurological phenotypes including episodic ataxia (EA2), spinocerebellar ataxia (SCA6), and familial hemiplegic migraine (FHM1). Epilepsy is poorly documented. We studied 18 patients (10 males) carrying de novo or inherited CACNA1A mutations, with median age of 2,5 years at epilepsy onset. Eight mutations were novel. Two variants known leading to gain of function (GOF) were found in 5 patients. Five other patients had non-sense variants leading to loss of function (LOF). Seizures were most often revealed by either status epilepticus (SE) (n = 8), eventually triggered by fever (n = 5), or absences/behavioural arrests (n = 7). Non-epileptic paroxysmal events were frequent and consisted in recurrent hemiplegic accesses (n = 9), jitteriness in the neonatal period (n = 6), and ocular paroxysmal events (n = 9). Most of the patients had early permanent cerebellar dysfunction (n = 16) and early moderate to severe global developmental delay (GDD)/intellectual deficiency (ID) (n = 17). MRI was often abnormal, with cerebellar (n = 8) and/or cerebral (n = 6) atrophy. Stroke-like occurred in 2 cases. Some antiepileptic drugs including topiramate, levetiracetam, lamotrigine and valproate were effective on seizures. Acetazolamide and calcium channel blockers were often effective when used. More than half of the patients had refractory epilepsy. CACNA1A mutation should be evoked in front of 2 main electro-clinical phenotypes that are associated with permanent cerebellar dysfunction and moderate to severe GDD/ID. The first one, found in all 5 patients with GOF variants, is characterized by intractable seizures, early and recurrent SE and hemiplegic accesses. The second, less severe, found in 5 patients with LOF variants, is characterized by refractory early onset absence seizures.
Topics: Ataxia; Calcium Channels; Child, Preschool; Epilepsy; Female; Humans; Male; Seizures; Spinocerebellar Ataxias
PubMed: 34102571
DOI: 10.1016/j.ejpn.2021.05.010 -
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 -
Cell Reports Apr 2022Lung progenitor cells are crucial for regeneration following injury, yet it is unclear whether lung progenitor cells can be functionally engrafted after transplantation....
Lung progenitor cells are crucial for regeneration following injury, yet it is unclear whether lung progenitor cells can be functionally engrafted after transplantation. We transplanted organoid cells derived from alveolar type II (AT2) cells enriched by SCA1-negative status (SNO) or multipotent SCA1-positive progenitor cells (SPO) into injured mouse lungs. Transplanted SNO cells are retained in the alveolar regions, whereas SPO cells incorporate into airway and alveolar regions. Single-cell transcriptomics demonstrate that transplanted SNO cells are comparable to native AT2 cells. Transplanted SPO cells exhibit transcriptional hallmarks of alveolar and airway cells, as well as transitional cell states identified in disease. Transplanted cells proliferate after re-injury of recipient mice and retain organoid-forming capacity. Thus, lung epithelial organoid cells exhibit progenitor cell functions after reintroduction to the lung. This study reveals methods to interrogate lung progenitor cell potential and model transitional cell states relevant to pathogenic features of lung disease in vivo.
Topics: Animals; Cell Differentiation; Epithelial Cells; Lung; Mice; Organoids; Spinocerebellar Ataxias; Stem Cells
PubMed: 35417699
DOI: 10.1016/j.celrep.2022.110662 -
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 -
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