Spinocerebellar ataxia: an update

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Abstract

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.

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The online version of this article (10.1007/s00415-018-9076-4) contains supplementary material, which is available to authorized users.

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Most cited references 109

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Continuous base identification for single-molecule nanopore DNA sequencing.

James Clarke, Hai-Chen Wu, Lakmal Jayasinghe … (2009)

A single-molecule method for sequencing DNA that does not require fluorescent labelling could reduce costs and increase sequencing speeds. An exonuclease enzyme might be used to cleave individual nucleotide molecules from the DNA, and when coupled to an appropriate detection system, these nucleotides could be identified in the correct order. Here, we show that a protein nanopore with a covalently attached adapter molecule can continuously identify unlabelled nucleoside 5'-monophosphate molecules with accuracies averaging 99.8%. Methylated cytosine can also be distinguished from the four standard DNA bases: guanine, adenine, thymine and cytosine. The operating conditions are compatible with the exonuclease, and the kinetic data show that the nucleotides have a high probability of translocation through the nanopore and, therefore, of not being registered twice. This highly accurate tool is suitable for integration into a system for sequencing nucleic acids and for analysing epigenetic modifications.

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Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.

Manuel Alvarez-Dolado, Ricardo Pardal, Jose M Garcia-Verdugo … (2003)

Recent studies have suggested that bone marrow cells possess a broad differentiation potential, being able to form new liver cells, cardiomyocytes and neurons. Several groups have attributed this apparent plasticity to 'transdifferentiation'. Others, however, have suggested that cell fusion could explain these results. Using a simple method based on Cre/lox recombination to detect cell fusion events, we demonstrate that bone-marrow-derived cells (BMDCs) fuse spontaneously with neural progenitors in vitro. Furthermore, bone marrow transplantation demonstrates that BMDCs fuse in vivo with hepatocytes in liver, Purkinje neurons in the brain and cardiac muscle in the heart, resulting in the formation of multinucleated cells. No evidence of transdifferentiation without fusion was observed in these tissues. These observations provide the first in vivo evidence for cell fusion of BMDCs with neurons and cardiomyocytes, raising the possibility that cell fusion may contribute to the development or maintenance of these key cell types.

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Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.

H T Orr, M Y Chung, S. Banfi … (1993)

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. There is a direct correlation between the size of the (CAG)n repeat expansion and the age-of-onset of SCA1, with larger alleles occurring in juvenile cases. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.

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Author and article information

Contributors

Roisin Sullivan: r.sullivan@ucl.ac.uk

Journal

Journal ID (nlm-ta): J Neurol

Journal ID (iso-abbrev): J. Neurol

Title: Journal of Neurology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0340-5354

ISSN (Electronic): 1432-1459

Publication date (Electronic): 3 October 2018

Publication date PMC-release: 3 October 2018

Publication date (Print): 2019

Volume: 266

Issue: 2

Pages: 533-544

Affiliations

ISNI 0000000121901201, GRID grid.83440.3b, Department of Neuromuscular Diseases, , UCL Queen’s Square Institute of Neurology, ; Queen’s Square House, Queen’s Square, London, WC1N 3BG UK

Article

Publisher ID: 9076

DOI: 10.1007/s00415-018-9076-4

PMC ID: 6373366

PubMed ID: 30284037

SO-VID: 72fa17ea-c561-4b9c-9326-5f23bb0fea75

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 27 July 2018

Date revision received : 21 September 2018

Date accepted : 25 September 2018

Funding

Funded by: Brain Research Trust

Award ID: 540051

Award Recipient : Emer O’Connor

Funded by: FundRef http://dx.doi.org/10.13039/501100000833, Rosetrees Trust;

Award ID: 516457

Award Recipient : Wai Yan Yau

Funded by: FundRef http://dx.doi.org/10.13039/501100000346, Ataxia UK;

Award ID: 516457

Award Recipient : Wai Yan Yau

Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;

Award ID: 54313

Award Recipient : Roisin Sullivan

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ScienceOpen disciplines: Neurology

Keywords: spinocerebellar ataxia,molecular diagnosis,next-generation sequencing

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ScienceOpen disciplines: Neurology

Keywords: spinocerebellar ataxia, molecular diagnosis, next-generation sequencing

Spinocerebellar ataxia: an update

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 109

Continuous base identification for single-molecule nanopore DNA sequencing.

Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.

Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.

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