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Spinocerebellar Ataxia (SCA): Molecular Mechanisms and Novel Treatment Strategies
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Spinocerebellar Ataxia (SCA): Molecular Mechanisms and Novel Treatment Strategies

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cells of the Nervous System".

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Editor

Dr. Maria do Carmo Costa

E-Mail Website
Collection Editor
Department of Neurology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
Interests: MJD/SCA3; polyglutamine diseases; function of polyglutamine proteins; therapeutic approaches for polyglutamine diseases; molecular mechanisms and biomarkers of neurodegeneration; genetics of dynamic repeat disorders

Topical Collection Information

Dear Colleagues,

Spinocerebellar ataxias (SCAs) are a group of autosomal dominant inherited diseases of usual onset in adult life. SCAs are phenotypically and genetically heterogeneous disorders with no currently available disease-modifying treatment.

While the major clinical signs of SCAs are progressive gait ataxia, typically accompanied by dysarthria and visual problems, several other symptoms can appear such as limb and trunk ataxia, tremor, rigidity, dystonia, bradykinesia, and cognitive impairment.

Presently, 48 SCAs can be discerned by the identified mutation or the chromosomal location of their associated disease genes. The most prevalent group of SCAs, accounting for more than 50% of the known SCAs, are caused by expansions of CAG repeats, encoding polyglutamine (polyQ) tracts in the disease proteins, and are therefore designated as polyQ SCAs. Other less-common SCAs are caused by the expansion of other nucleotide repeats, point mutations, deletions, insertions, and duplications in the disease genes.

Overall, research efforts have been showing that whereas SCAs may share disease mechanisms that can be therapeutically targeted for all SCAs, given the heterogenous genetic causes, specific therapeutic strategies for each SCA or subgroup of SCAs may be comparatively more successful. Preclinical research—mostly for the polyQ SCAs—has indeed generated some therapeutic agents that are about to approaching testing in patients.

In this Topical Collection we invite all scientists working on spinocerebellar ataxias to contribute original research articles, reviews, communications, and short perspective articles on all aspects related to molecular mechanisms and novel treatment strategies for SCAs. We particularly welcome articles describing mechanistic insights at the molecular, cellular, or organismal level, as well as those providing translational value.

Dr. Maria do Carmo Costa
Collection Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • spinocerebellar ataxia
  • polyglutamine
  • therapeutic approaches
  • disease mechanisms

Published Papers (10 papers)

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2023

Jump to: 2022

16 pages, 3219 KiB  
Article
Tissue-Specific Vulnerability to Apoptosis in Machado-Joseph Disease
by Ana F. Ferreira, Mafalda Raposo, Emily D. Shaw, Naila S. Ashraf, Filipa Medeiros, Maria de Fátima Brilhante, Matthew Perkins, João Vasconcelos, Teresa Kay, Maria do Carmo Costa and Manuela Lima
Cells 2023, 12(10), 1404; https://doi.org/10.3390/cells12101404 - 17 May 2023
Viewed by 1321
Abstract
Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of [...] Read more.
Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD and to evaluate if expression alterations of specific apoptosis genes/proteins can be used as transcriptional biomarkers of disease, the expression levels of BCL2, BAX and TP53 and the BCL2/BAX ratio (an indicator of susceptibility to apoptosis) were assessed in blood and post-mortem brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood BCL2 transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood BAX transcripts and decreased BCL2/BAX ratio are associated with earlier onset of disease, indicating a possible association with MJD pathogenesis. Post-mortem MJD brains show increased BCL2/BAX transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood BCL2 and TP53 transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood BCL2, BAX, and TP53 transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue-dependent behavior is partially replicated in a MJD mouse model. Full article
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2022

Jump to: 2023

16 pages, 1931 KiB  
Article
Sleep Alterations in a Mouse Model of Spinocerebellar Ataxia Type 3
by Maria-Efstratia Tsimpanouli, Anjesh Ghimire, Anna J. Barget, Ridge Weston, Henry L. Paulson, Maria do Carmo Costa and Brendon O. Watson
Cells 2022, 11(19), 3132; https://doi.org/10.3390/cells11193132 - 05 Oct 2022
Cited by 2 | Viewed by 1822
Abstract
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder showing progressive neuronal loss in several brain areas and a broad spectrum of motor and non-motor symptoms, including ataxia and altered sleep. While sleep disturbances are known to play pathophysiologic roles in other neurodegenerative [...] Read more.
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder showing progressive neuronal loss in several brain areas and a broad spectrum of motor and non-motor symptoms, including ataxia and altered sleep. While sleep disturbances are known to play pathophysiologic roles in other neurodegenerative disorders, their impact on SCA3 is unknown. Using spectrographic measurements, we sought to quantitatively characterize sleep electroencephalography (EEG) in SCA3 transgenic mice with confirmed disease phenotype. We first measured motor phenotypes in 18–31-week-old homozygous SCA3 YACMJD84.2 mice and non-transgenic wild-type littermate mice during lights-on and lights-off periods. We next implanted electrodes to obtain 12-h (zeitgeber time 0-12) EEG recordings for three consecutive days when the mice were 26–36 weeks old. EEG-based spectroscopy showed that compared to wild-type littermates, SCA3 homozygous mice display: (i) increased duration of rapid-eye movement sleep (REM) and fragmentation in all sleep and wake states; (ii) higher beta power oscillations during REM and non-REM (NREM); and (iii) additional spectral power band alterations during REM and wake. Our data show that sleep architecture and EEG spectral power are dysregulated in homozygous SCA3 mice, indicating that common sleep-related etiologic factors may underlie mouse and human SCA3 phenotypes. Full article
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13 pages, 2383 KiB  
Article
Loss of Flocculus Purkinje Cell Firing Precision Leads to Impaired Gaze Stabilization in a Mouse Model of Spinocerebellar Ataxia Type 6 (SCA6)
by Hui Ho Vanessa Chang, Anna A. Cook, Alanna J. Watt and Kathleen E. Cullen
Cells 2022, 11(17), 2739; https://doi.org/10.3390/cells11172739 - 02 Sep 2022
Cited by 4 | Viewed by 2032
Abstract
Spinocerebellar Ataxia Type 6 (SCA6) is a mid-life onset neurodegenerative disease characterized by progressive ataxia, dysarthria, and eye movement impairment. This autosomal dominant disease is caused by the expansion of a CAG repeat tract in the CACNA1A gene that encodes the α1A subunit [...] Read more.
Spinocerebellar Ataxia Type 6 (SCA6) is a mid-life onset neurodegenerative disease characterized by progressive ataxia, dysarthria, and eye movement impairment. This autosomal dominant disease is caused by the expansion of a CAG repeat tract in the CACNA1A gene that encodes the α1A subunit of the P/Q type voltage-gated Ca2+ channel. Mouse models of SCA6 demonstrate impaired locomotive function and reduced firing precision of cerebellar Purkinje in the anterior vermis. Here, to further assess deficits in other cerebellar-dependent behaviors, we characterized the oculomotor phenotype of a knock-in mouse model with hyper-expanded polyQ repeats (SCA684Q). We found a reduction in the efficacy of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) in SCA6 mutant mice, without a change in phase, compared to their litter-matched controls. Additionally, VOR motor learning was significantly impaired in SCA684Q mice. Given that the floccular lobe of the cerebellum plays a vital role in the generation of OKR and VOR calibration and motor learning, we investigated the firing behavior and morphology of floccular cerebellar Purkinje cells. Overall, we found a reduction in the firing precision of floccular lobe Purkinje cells but no morphological difference between SCA684Q and wild-type mice. Taken together, our findings establish that gaze stabilization and motor learning are impaired in SCA684Q mice and suggest that altered cerebellar output contributes to these deficits. Full article
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17 pages, 3748 KiB  
Article
Identifying Disease Signatures in the Spinocerebellar Ataxia Type 1 Mouse Cortex
by Kimberly Luttik, Victor Olmos, Ashley Owens, Aryaan Khan, Joy Yun, Terri Driessen and Janghoo Lim
Cells 2022, 11(17), 2632; https://doi.org/10.3390/cells11172632 - 24 Aug 2022
Cited by 5 | Viewed by 2257
Abstract
The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is known to lead to the progressive degeneration of specific neuronal populations, including cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. The disease-causing protein ataxin-1 is fairly ubiquitously [...] Read more.
The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is known to lead to the progressive degeneration of specific neuronal populations, including cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. The disease-causing protein ataxin-1 is fairly ubiquitously expressed throughout the brain and spinal cord, but most studies have primarily focused on the role of ataxin-1 in the cerebellum and brainstem. Therefore, the functions of ataxin-1 and the effects of SCA1 mutations in other brain regions including the cortex are not well-known. Here, we characterized pathology in the motor cortex of a SCA1 mouse model and performed RNA sequencing in this brain region to investigate the impact of mutant ataxin-1 towards transcriptomic alterations. We identified progressive cortical pathology and significant transcriptomic changes in the motor cortex of a SCA1 mouse model. We also identified progressive, region-specific, colocalization of p62 protein with mutant ataxin-1 aggregates in broad brain regions, but not the cerebellum or brainstem. A cross-regional comparison of the SCA1 cortical and cerebellar transcriptomic changes identified both common and unique gene expression changes between the two regions, including shared synaptic dysfunction and region-specific kinase regulation. These findings suggest that the cortex is progressively impacted via both shared and region-specific mechanisms in SCA1. Full article
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18 pages, 5314 KiB  
Article
Pathogenetic Mechanisms Underlying Spinocerebellar Ataxia Type 3 Are Altered in Primary Oligodendrocyte Culture
by Kristen H. Schuster, Alexandra F. Putka and Hayley S. McLoughlin
Cells 2022, 11(16), 2615; https://doi.org/10.3390/cells11162615 - 22 Aug 2022
Cited by 7 | Viewed by 2426
Abstract
Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of [...] Read more.
Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of the of the earliest and most robust changes in vulnerable regions of the SCA3 mouse brain. However, the cell- and disease-specific mechanisms that underlie oligodendrocyte dysfunction remain poorly understood and are difficult to isolate in vivo. In this study, we used primary oligodendrocyte cultures to determine how known pathogenic SCA3 mechanisms affect this cell type. We isolated oligodendrocyte progenitor cells from 5- to 7-day-old mice that overexpress human mutant ATXN3 or lack mouse ATXN3 and differentiated them for up to 5 days in vitro. Utilizing immunocytochemistry, we characterized the contributions of ATXN3 toxic gain-of-function and loss-of-function in oligodendrocyte maturation, protein quality pathways, DNA damage signaling, and methylation status. We illustrate the utility of primary oligodendrocyte culture for elucidating cell-specific pathway dysregulation relevant to SCA3. Given recent work demonstrating disease-associated oligodendrocyte signatures in other neurodegenerative diseases, this novel model has broad applicability in revealing mechanistic insights of oligodendrocyte contribution to pathogenesis. Full article
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14 pages, 2517 KiB  
Article
Indirect Negative Effect of Mutant Ataxin-1 on Short- and Long-Term Synaptic Plasticity in Mouse Models of Spinocerebellar Ataxia Type 1
by Anton N. Shuvaev, Olga S. Belozor, Oleg I. Mozhei, Andrey N. Shuvaev, Yana V. Fritsler, Elena D. Khilazheva, Angelina I. Mosyagina, Hirokazu Hirai, Anja G. Teschemacher and Sergey Kasparov
Cells 2022, 11(14), 2247; https://doi.org/10.3390/cells11142247 - 20 Jul 2022
Cited by 5 | Viewed by 1825
Abstract
Spinocerebellar ataxia type 1 (SCA1) is an intractable progressive neurodegenerative disease that leads to a range of movement and motor defects and is eventually lethal. Purkinje cells (PC) are typically the first to show signs of degeneration. SCA1 is caused by an expansion [...] Read more.
Spinocerebellar ataxia type 1 (SCA1) is an intractable progressive neurodegenerative disease that leads to a range of movement and motor defects and is eventually lethal. Purkinje cells (PC) are typically the first to show signs of degeneration. SCA1 is caused by an expansion of the polyglutamine tract in the ATXN1 gene and the subsequent buildup of mutant Ataxin-1 protein. In addition to its toxicity, mutant Ataxin-1 protein interferes with gene expression and signal transduction in cells. Recently, it is evident that ATXN1 is not only expressed in neurons but also in glia, however, it is unclear the extent to which either contributes to the overall pathology of SCA1. There are various ways to model SCA1 in mice. Here, functional deficits at cerebellar synapses were investigated in two mouse models of SCA1 in which mutant ATXN1 is either nonspecifically expressed in all cell types of the cerebellum (SCA1 knock-in (KI)), or specifically in Bergmann glia with lentiviral vectors expressing mutant ATXN1 under the control of the astrocyte-specific GFAP promoter. We report impairment of motor performance in both SCA1 models. In both cases, prominent signs of astrocytosis were found using immunohistochemistry. Electrophysiological experiments revealed alteration of presynaptic plasticity at synapses between parallel fibers and PCs, and climbing fibers and PCs in SCA1 KI mice, which is not observed in animals expressing mutant ATXN1 solely in Bergmann glia. In contrast, short- and long-term synaptic plasticity was affected in both SCA1 KI mice and glia-targeted SCA1 mice. Thus, non-neuronal mechanisms may underlie some aspects of SCA1 pathology in the cerebellum. By combining the outcomes of our current work with our previous data from the B05 SCA1 model, we further our understanding of the mechanisms of SCA1. Full article
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25 pages, 7892 KiB  
Article
Microglial Depletion Has No Impact on Disease Progression in a Mouse Model of Machado–Joseph Disease
by Ana Bela Campos, Sara Duarte-Silva, Bruno Fernandes, Bárbara Coimbra, Jonas Campos, Daniela Monteiro-Fernandes, Andreia Teixeira-Castro, António Francisco Ambrósio and Patrícia Maciel
Cells 2022, 11(13), 2022; https://doi.org/10.3390/cells11132022 - 25 Jun 2022
Cited by 3 | Viewed by 1819
Abstract
Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder (ND). While most research in NDs has been following a neuron-centric point of view, microglia are now recognized as crucial in the brain. Previous work revealed [...] Read more.
Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder (ND). While most research in NDs has been following a neuron-centric point of view, microglia are now recognized as crucial in the brain. Previous work revealed alterations that point to an increased activation state of microglia in the brain of CMVMJD135 mice, a MJD mouse model that replicates the motor symptoms and neuropathology of the human condition. Here, we investigated the extent to which microglia are actively contributing to MJD pathogenesis and symptom progression. For this, we used PLX3397 to reduce the number of microglia in the brain of CMVMJD135 mice. In addition, a set of statistical and machine learning models were further implemented to analyze the impact of PLX3397 on the morphology of the surviving microglia. Then, a battery of behavioral tests was used to evaluate the impact of microglial depletion on the motor phenotype of CMVMJD135 mice. Although PLX3397 treatment substantially reduced microglia density in the affected brain regions, it did not affect the motor deficits seen in CMVMJD135 mice. In addition to reducing the number of microglia, the treatment with PLX3397 induced morphological changes suggestive of activation in the surviving microglia, the microglia of wild-type animals becoming similar to those of CMVMJD135 animals. These results suggest that microglial cells are not key contributors for MJD progression. Furthermore, the impact of PLX3397 on microglial activation should be taken into account in the interpretation of findings of ND modification seen upon treatment with this CSF1R inhibitor. Full article
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21 pages, 6713 KiB  
Article
A Robust Assay to Monitor Ataxin-3 Amyloid Fibril Assembly
by Francisco Figueiredo, Mónica Lopes-Marques, Bruno Almeida, Nena Matscheko, Pedro M. Martins, Alexandra Silva and Sandra Macedo-Ribeiro
Cells 2022, 11(12), 1969; https://doi.org/10.3390/cells11121969 - 19 Jun 2022
Cited by 2 | Viewed by 2723
Abstract
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine repeat in the protein ataxin-3, which is deposited as intracellular aggregates in affected brain regions. Despite the controversial role of ataxin-3 amyloid structures in SCA3 pathology, the identification of molecules [...] Read more.
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine repeat in the protein ataxin-3, which is deposited as intracellular aggregates in affected brain regions. Despite the controversial role of ataxin-3 amyloid structures in SCA3 pathology, the identification of molecules with the capacity to prevent aberrant self-assembly and stabilize functional conformation(s) of ataxin-3 is a key to the development of therapeutic solutions. Amyloid-specific kinetic assays are routinely used to measure rates of protein self-assembly in vitro and are employed during screening for fibrillation inhibitors. The high tendency of ataxin-3 to assemble into oligomeric structures implies that minor changes in experimental conditions can modify ataxin-3 amyloid assembly kinetics. Here, we determine the self-association rates of ataxin-3 and present a detailed study of the aggregation of normal and pathogenic ataxin-3, highlighting the experimental conditions that should be considered when implementing and validating ataxin-3 amyloid progress curves in different settings and in the presence of ataxin-3 interactors. This assay provides a unique and robust platform to screen for modulators of the first steps of ataxin-3 aggregation—a starting point for further studies with cell and animal models of SCA3. Full article
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18 pages, 5548 KiB  
Article
Drosophila as a Model of Unconventional Translation in Spinocerebellar Ataxia Type 3
by Sean L. Johnson, Matthew V. Prifti, Alyson Sujkowski, Kozeta Libohova, Jessica R. Blount, Luke Hong, Wei-Ling Tsou and Sokol V. Todi
Cells 2022, 11(7), 1223; https://doi.org/10.3390/cells11071223 - 04 Apr 2022
Cited by 8 | Viewed by 2441
Abstract
RNA toxicity contributes to diseases caused by anomalous nucleotide repeat expansions. Recent work demonstrated RNA-based toxicity from repeat-associated, non-AUG-initiated translation (RAN translation). RAN translation occurs around long nucleotide repeats that form hairpin loops, allowing for translation initiation in the absence of a start [...] Read more.
RNA toxicity contributes to diseases caused by anomalous nucleotide repeat expansions. Recent work demonstrated RNA-based toxicity from repeat-associated, non-AUG-initiated translation (RAN translation). RAN translation occurs around long nucleotide repeats that form hairpin loops, allowing for translation initiation in the absence of a start codon that results in potentially toxic, poly-amino acid repeat-containing proteins. Discovered in Spinocerebellar Ataxia Type (SCA) 8, RAN translation has been documented in several repeat-expansion diseases, including in the CAG repeat-dependent polyglutamine (polyQ) disorders. The ATXN3 gene, which causes SCA3, also known as Machado–Joseph Disease (MJD), contains a CAG repeat that is expanded in disease. ATXN3 mRNA possesses features linked to RAN translation. In this paper, we examined the potential contribution of RAN translation to SCA3/MJD in Drosophila by using isogenic lines that contain homomeric or interrupted CAG repeats. We did not observe unconventional translation in fly neurons or glia. However, our investigations indicate differential toxicity from ATXN3 protein-encoding mRNA that contains pure versus interrupted CAG repeats. Additional work suggests that this difference may be due in part to toxicity from homomeric CAG mRNA. We conclude that Drosophila is not suitable to model RAN translation for SCA3/MJD, but offers clues into the potential pathogenesis stemming from CAG repeat-containing mRNA in this disorder. Full article
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23 pages, 2025 KiB  
Review
Molecular Mechanisms in Pentanucleotide Repeat Diseases
by Joana R. Loureiro, Ana F. Castro, Ana S. Figueiredo and Isabel Silveira
Cells 2022, 11(2), 205; https://doi.org/10.3390/cells11020205 - 08 Jan 2022
Cited by 16 | Viewed by 3789
Abstract
The number of neurodegenerative diseases resulting from repeat expansion has increased extraordinarily in recent years. In several of these pathologies, the repeat can be transcribed in RNA from both DNA strands producing, at least, one toxic RNA repeat that causes neurodegeneration by a [...] Read more.
The number of neurodegenerative diseases resulting from repeat expansion has increased extraordinarily in recent years. In several of these pathologies, the repeat can be transcribed in RNA from both DNA strands producing, at least, one toxic RNA repeat that causes neurodegeneration by a complex mechanism. Recently, seven diseases have been found caused by a novel intronic pentanucleotide repeat in distinct genes encoding proteins highly expressed in the cerebellum. These disorders are clinically heterogeneous being characterized by impaired motor function, resulting from ataxia or epilepsy. The role that apparently normal proteins from these mutant genes play in these pathologies is not known. However, recent advances in previously known spinocerebellar ataxias originated by abnormal non-coding pentanucleotide repeats point to a gain of a toxic function by the pathogenic repeat-containing RNA that abnormally forms nuclear foci with RNA-binding proteins. In cells, RNA foci have been shown to be formed by phase separation. Moreover, the field of repeat expansions has lately achieved an extraordinary progress with the discovery that RNA repeats, polyglutamine, and polyalanine proteins are crucial for the formation of nuclear membraneless organelles by phase separation, which is perturbed when they are expanded. This review will cover the amazing advances on repeat diseases. Full article
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