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Spinocerebellar Ataxias: Uncovering Their Molecular Mechanisms, Biomarker Development, and Therapies
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Spinocerebellar Ataxias: Uncovering Their Molecular Mechanisms, Biomarker Development, and Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 April 2025 | Viewed by 4329

Special Issue Editor

Dr. Anna Sulek

E-Mail Website
Guest Editor
Faculty of Medicine, Lazarski University, 02-662 Warsaw, Poland
Interests: neurogenetics; rare disorders; microsatellite repeat expansion

Special Issue Information

Dear Colleagues,

Spinocerebellar ataxias are neurodegenerative diseases that have long attracted the interest of researchers from various fields. Representing particular disease entities, some with a clearly defined genetic basis, they constitute a group of diseases with various molecular disorders that ultimately lead to the same effect: the death of neurons. In the treatment of cerebellar ataxias, the validation of clinical trial results plays an important role; hence, emphasis has been placed on the search for biomarkers that are reliable indicators of a patient’s clinical condition. The immense need to offer effective therapies may result in the advancement of research, leading to symptomatic, causal, or personalized therapies with the hope of achieving significant effects.

This Special Issue is devoted to disseminating research results on the molecular mechanisms underlying these diseases and research on their potential therapeutic targets.

We welcome everyone that may be interested in these issues to publish articles in this Special Issue, “Spinocerebellar Ataxias: Uncovering Their Molecular Mechanisms, Biomarker Development, and Therapies”, considering this group of rare neurodegenerative diseases.

Dr. Anna Sulek
Guest 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 special issue 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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • biomarker
  • neurodegeneration
  • preclinical models
  • transcriptomics
  • proteomics
  • microRNA
  • iPSC
  • dynamic mutations

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Published Papers (4 papers)

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Research

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13 pages, 1963 KiB  
Article
Altered Cellular Metabolism Is a Consequence of Loss of the Ataxia-Linked Protein Sacsin
by Laura Perna, Grace Salsbury, Mohammed Dushti, Christopher J. Smith, Valle Morales, Katiuscia Bianchi, Gabor Czibik and J. Paul Chapple
Int. J. Mol. Sci. 2024, 25(24), 13242; https://doi.org/10.3390/ijms252413242 - 10 Dec 2024
Viewed by 379
Abstract
Mitochondrial dysfunction is implicated in the pathogenesis of the neurological condition autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), yet precisely how the mitochondrial metabolism is affected is unknown. Thus, to better understand changes in the mitochondrial metabolism caused by loss of the sacsin [...] Read more.
Mitochondrial dysfunction is implicated in the pathogenesis of the neurological condition autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), yet precisely how the mitochondrial metabolism is affected is unknown. Thus, to better understand changes in the mitochondrial metabolism caused by loss of the sacsin protein (encoded by the SACS gene, which is mutated in ARSACS), we performed mass spectrometry-based tracer analysis, with both glucose- and glutamine-traced carbon. Comparing the metabolite profiles between wild-type and sacsin-knockout cell lines revealed increased reliance on aerobic glycolysis in sacsin-deficient cells, as evidenced by the increase in lactate and reduction of glucose. Moreover, sacsin knockout cells differentiated towards a neuronal phenotype had increased levels of tricarboxylic acid cycle metabolites relative to the controls. We also observed disruption in the glutaminolysis pathway in differentiated and undifferentiated cells in the absence of sacsin. In conclusion, this work demonstrates consequences for cellular metabolism associated with a loss of sacsin, which may be relevant to ARSACS. Full article
(This article belongs to the Special Issue Spinocerebellar Ataxias: Uncovering Their Molecular Mechanisms, Biomarker Development, and Therapies)
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12 pages, 1276 KiB  
Article
Kv3.3 Expression Enhanced by a Novel Variant in the Kozak Sequence of KCNC3
by Marlen Colleen Reis, Frauke Härtel, Antje Maria Richter, Michaela Weiß, Lea-Theresa Mösle, Reinhard Heinrich Dammann and Dagmar Nolte
Int. J. Mol. Sci. 2024, 25(22), 12444; https://doi.org/10.3390/ijms252212444 - 20 Nov 2024
Viewed by 789
Abstract
Pathogenic variants in KCNC3, which encodes the voltage-gated potassium channel Kv3.3, are associated with spinocerebellar ataxia type 13. SCA13 is a neurodegenerative disease characterized by ataxia, dysarthria and oculomotor dysfunction, often in combination with other signs and symptoms such as cognitive impairment. [...] Read more.
Pathogenic variants in KCNC3, which encodes the voltage-gated potassium channel Kv3.3, are associated with spinocerebellar ataxia type 13. SCA13 is a neurodegenerative disease characterized by ataxia, dysarthria and oculomotor dysfunction, often in combination with other signs and symptoms such as cognitive impairment. Known disease-causing variants are localized in the protein coding regions and predominantly in the transmembrane and voltage sensing domains. In a patient with an ataxic movement disorder and progressive cognitive decline, the c.-6C>A variant was detected in the Kozak sequence of KCNC3. The Kozak sequence is responsible for efficient initiation of translation. Functional analysis of the new c.-6C>A variant and the upstream 5’-UTR region of KCNC3 by luciferase assays, quantitative PCR and methylation analysis shows increased protein expression but no effect on transcription rate. Therefore, increased translation initiation of KCNC3 transcripts compared to wild-type Kozak sequence seems to be the cause of the increased expression. Variants in the regulatory elements of disease-causing genes probably play an underestimated role. Full article
(This article belongs to the Special Issue Spinocerebellar Ataxias: Uncovering Their Molecular Mechanisms, Biomarker Development, and Therapies)
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14 pages, 4824 KiB  
Article
Compound Heterozygous Mutations of SACS in a Korean Cohort Study of Charcot-Marie-Tooth Disease Concurrent Cerebellar Ataxia and Spasticity
by Byung Kwon Pi, Yeon Hak Chung, Hyun Su Kim, Soo Hyun Nam, Ah Jin Lee, Da Eun Nam, Hyung Jun Park, Sang Beom Kim, Ki Wha Chung and Byung-Ok Choi
Int. J. Mol. Sci. 2024, 25(12), 6378; https://doi.org/10.3390/ijms25126378 - 9 Jun 2024
Viewed by 1043
Abstract
Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole [...] Read more.
Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity. Full article
(This article belongs to the Special Issue Spinocerebellar Ataxias: Uncovering Their Molecular Mechanisms, Biomarker Development, and Therapies)
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Review

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12 pages, 1241 KiB  
Review
Specific Biomarkers in Spinocerebellar Ataxia Type 3: A Systematic Review of Their Potential Uses in Disease Staging and Treatment Assessment
by Alexandra E. Soto-Piña, Caroline C. Pulido-Alvarado, Jaroslaw Dulski, Zbigniew K. Wszolek and Jonathan J. Magaña
Int. J. Mol. Sci. 2024, 25(15), 8074; https://doi.org/10.3390/ijms25158074 - 24 Jul 2024
Viewed by 1517
Abstract
Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 [...] Read more.
Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one. Full article
(This article belongs to the Special Issue Spinocerebellar Ataxias: Uncovering Their Molecular Mechanisms, Biomarker Development, and Therapies)
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