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Cells May 2022Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from elements,... (Review)
Review
Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from elements, and often result in autosomal dominant or recessive phenotypes with underlying cerebellar neuropathology. When transcribed (potentially bidirectionally), the expanded RNA forms complex secondary and tertiary structures that can give rise to RNA-mediated toxicity, including protein sequestration, pentapeptide synthesis, and mRNA dysregulation. Since several of these diseases have recently been discovered, our understanding of their pathological mechanisms is limited, and their therapeutic interventions underexplored. This review aims to highlight new in vitro and in vivo insights into these incurable diseases.
Topics: Ataxia; Cerebellum; Humans; Microsatellite Repeats; RNA; Spinocerebellar Ataxias
PubMed: 35563872
DOI: 10.3390/cells11091567 -
Stem Cell Reviews and Reports Feb 2022Dominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the... (Review)
Review
Dominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the cerebellum as their main hallmark. Although animal and cell models have been highly instrumental for our current insight into the underlying disease mechanisms of these neurodegenerative disorders, they do not offer the full human genetic and physiological context. The advent of human induced pluripotent stem cells (hiPSCs) and protocols to differentiate these into essentially every cell type allows us to closely model SCAs in a human context. In this review, we systematically summarize recent findings from studies using hiPSC-based modelling of SCAs, and discuss what knowledge has been gained from these studies. We conclude that hiPSC-based models are a powerful tool for modelling SCAs as they contributed to new mechanistic insights and have the potential to serve the development of genetic therapies. However, the use of standardized methods and multiple clones of isogenic lines are essential to increase validity and reproducibility of the insights gained.
Topics: Animals; Cerebellum; Genetic Therapy; Humans; Induced Pluripotent Stem Cells; Reproducibility of Results; Spinocerebellar Ataxias
PubMed: 34031815
DOI: 10.1007/s12015-021-10184-0 -
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 -
Brain : a Journal of Neurology Jul 2018The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia...
The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements. Here we demonstrate the segregation of an unstable intronic ATTTC pentanucleotide repeat mutation within the 1p32 5' non-coding regulatory region of the gene encoding the reelin adaptor protein DAB1, implicated in neuronal migration, as the causative genetic defect of the disease in four Spanish SCA37 families. We describe the clinical-genetic correlation and the first SCA37 neuropathological findings caused by dysregulation of cerebellar DAB1 expression. Post-mortem neuropathology of two patients with SCA37 revealed severe loss of Purkinje cells with abundant astrogliosis, empty baskets, occasional axonal spheroids, and hypertrophic fibres by phosphorylated neurofilament immunostaining in the cerebellar cortex. The remaining cerebellar Purkinje neurons showed loss of calbindin immunoreactivity, aberrant dendrite arborization, nuclear pathology including lobulation, irregularity, and hyperchromatism, and multiple ubiquitinated perisomatic granules immunostained for DAB1. A subpopulation of Purkinje cells was found ectopically mispositioned within the cerebellar cortex. No significant neuropathological alterations were identified in other brain regions in agreement with a pure cerebellar syndrome. Importantly, we found that the ATTTC repeat mutation dysregulated DAB1 expression and induced an RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the SCA37 cerebellum. This study reveals the unstable ATTTC repeat mutation within the DAB1 gene as the underlying genetic cause and provides evidence of reelin-DAB1 signalling dysregulation in the spinocerebellar ataxia type 37.
Topics: Adaptor Proteins, Signal Transducing; Adult; Ataxia; Cell Adhesion Molecules, Neuronal; Cerebellum; Extracellular Matrix Proteins; Female; Humans; Male; Microsatellite Repeats; Mutation; Nerve Tissue Proteins; Nervous System Diseases; Neuropathology; Pedigree; Purkinje Cells; Reelin Protein; Serine Endopeptidases; Spinocerebellar Ataxias; Spinocerebellar Degenerations
PubMed: 29939198
DOI: 10.1093/brain/awy137 -
Neuroscience Letters Jan 2019The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35... (Review)
Review
The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35 functionally diverse spinocerebellar ataxia genes have been identified. The main question that remains yet unsolved is why do some many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? To address this question it is important to identify intrinsic pathways important for Purkinje Cell function and survival. In this review, we discuss the current consensus on shared mechanisms underlying the pervasive Purkinje Cell loss in spinocerebellar ataxia. Additionally, using recently published cell type specific expression data, we identified several Purkinje Cell-specific genes and discuss how the corresponding pathways might underlie the vulnerability of Purkinje Cells in response to the diverse genetic insults causing spinocerebellar ataxia.
Topics: Animals; Cerebellum; Humans; Nerve Degeneration; Purkinje Cells; Signal Transduction; Spinocerebellar Ataxias
PubMed: 29421540
DOI: 10.1016/j.neulet.2018.02.004 -
Revue Neurologique May 2024Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset... (Review)
Review
Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.
Topics: Humans; Spinocerebellar Ataxias; Age of Onset; Cerebellar Ataxia; Fibroblast Growth Factors; Spinocerebellar Degenerations
PubMed: 38609751
DOI: 10.1016/j.neurol.2024.03.007 -
Annals of Clinical and Translational... Apr 2022To quantitatively evaluate upper limb ataxia using a novel pen-like sensor device in patients with spinocerebellar ataxia (SCA) and to assess its validity, reliability,...
OBJECTIVE
To quantitatively evaluate upper limb ataxia using a novel pen-like sensor device in patients with spinocerebellar ataxia (SCA) and to assess its validity, reliability, and sensitivity to disease progression.
METHODS
We designed a cross-sectional and longitudinal study of patients with SCA and healthy controls. Upper limb ataxia was evaluated using a device that measures the three-dimensional position every 10 msec. Participants were instructed to move a pen-like part of the device iteratively between two buttons. We evaluated the time, length, velocity, and variation coefficient of the stroke, and calculated the distortion index using the mean squared error. The following scales were also evaluated: Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the nine-hole pegboard test. Subjects were followed 12 months after the baseline evaluation.
RESULTS
A total of 42 patients with SCA and 33 healthy controls were enrolled and evaluated. For all ataxia indices measured using the device there were significant differences between healthy controls and patients with SCA. Among the ataxia indices, the distortion index showed the strongest correlation with the SARA and ICARS upper limb score (Pearson's r = 0.647 and 0.722, respectively). Test-retest reliability was high for most of the ataxia indices. In the longitudinal analysis, the distortion index showed high standardized response mean and adjusted effect size, regardless of disease severity.
INTERPRETATION
Our study demonstrated that the distortion index is a reliable functional marker that is sensitive to longitudinal change in patients with SCA.
Topics: Ataxia; Cerebellar Ataxia; Cross-Sectional Studies; Humans; Longitudinal Studies; Reproducibility of Results; Spinocerebellar Ataxias
PubMed: 35293156
DOI: 10.1002/acn3.51528 -
Neurologia I Neurochirurgia Polska 2017Spinocerebellar ataxia 15 (SCA15) is a clinically heterogeneous movement disorder characterized by the adult onset of slowly progressive cerebellar ataxia. ITPR1 is the... (Review)
Review
Spinocerebellar ataxia 15 (SCA15) is a clinically heterogeneous movement disorder characterized by the adult onset of slowly progressive cerebellar ataxia. ITPR1 is the SCA15 causative gene. However, despite numerous reports of genetically-confirmed SCA15, phenotypic uncertainty persists. We reviewed the phenotypes of 60 patients for whom SCA15 was confirmed by the presence of a genetic deletion involving ITPR1. The most prevalent symptoms were gait ataxia (88.3%), dysarthria (75.0%), nystagmus (73.3%), and limb ataxia (71.7%). We also present a novel SCA15 phenotype in a woman with an ITPR1 variant found to have hydrocephalus that improved with ventriculoperitoneal shunting. This is the first reported case of hydrocephalus associated with SCA15. In this review, we analyzed previously reported SCA15 phenotypes and present a novel SCA15 phenotype. We also address important considerations for evaluating patients with complex hereditary movement disorders.
Topics: Female; Humans; Hydrocephalus; Middle Aged; Phenotype; Spinocerebellar Ataxias
PubMed: 27908616
DOI: 10.1016/j.pjnns.2016.10.006 -
Human Genomics Jul 2022Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein. The pathogenic mechanism resulting in...
BACKGROUND
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein. The pathogenic mechanism resulting in SCA1 is still unclear. Protein-protein interactions affect the function and stability of ataxin-1.
METHODS
Wild-type and mutant ataxin-1 were expressed in HEK-293T cells. The levels of expression were assessed using real-time polymerase chain reaction (PCR) and Western blots. Co-immunoprecipitation was done in HEK-293T cells expressing exogenous wild-type and mutant ataxin-1 using anti-Flag antibody following by tandem affinity purification in order to study protein-protein interactions. The candidate interacting proteins were validated by immunoprecipitation. Chromatin immunoprecipitation and high-throughput sequencing and RNA immunoprecipitation and high-throughput sequencing were performed using HEK-293T cells expressing wild-type or mutant ataxin-1.
RESULTS
In this study using HEK-293T cells, we found that wild-type ataxin-1 interacted with MCM2, GNAS, and TMEM206, while mutant ataxin-1 lost its interaction with MCM2, GNAS, and TMEM206. Two ataxin-1 binding targets containing the core GGAG or AAAT were identified in HEK-293T cells using ChIP-seq. Gene Ontology analysis of the top ataxin-1 binding genes identified SLC6A15, NTF3, KCNC3, and DNAJC6 as functional genes in neurons in vitro. Ataxin-1 also was identified as an RNA-binding protein in HEK-293T cells using RIP-seq, but the polyglutamine expansion in the ataxin-1 had no direct effects on the RNA-binding activity of ataxin-1.
CONCLUSIONS
An expanded polyglutamine tract in ataxin-1 might interfere with protein-protein or protein-DNA interactions but had little effect on protein-RNA interactions. This study suggested that the dysfunction of protein-protein or protein-DNA interactions is involved in the pathogenesis of SCA1.
Topics: Amino Acid Transport Systems, Neutral; Ataxin-1; Ataxins; Humans; Nerve Tissue Proteins; Nuclear Proteins; RNA; Spinocerebellar Ataxias
PubMed: 35906672
DOI: 10.1186/s40246-022-00404-0 -
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