Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies

Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and accou...

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Bibliographic Details
Published in:Biomedicines 2021-10, Vol.9 (11), p.1499
Main Authors: McIntosh, Craig S., Li, Dunhui, Wilton, Steve D., Aung-Htut, May T.
Format: Article
Language:English
Subjects:
Antioxidants
Antisense oligonucleotides
Antisense therapy
Ataxia
Autophagy
Biomarkers
Clinical trials
Disease
expansion diseases
Gait
Genes
Huntingtons disease
Machado-Joseph disease
Mitochondria
Mutation
Neural coding
Neurodegeneration
Neurological diseases
Oxidative stress
Pathogenesis
Phagocytosis
Polyglutamine
Proteasomes
Proteins
Review
Spinocerebellar ataxia
Trinucleotide repeat diseases
Trinucleotide repeats
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Summary:Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and account for a larger group of disorders simply known as polyglutamine disorders, which also includes Huntington’s disease. These diseases are typically characterised by progressive ataxia, speech and swallowing difficulties, lack of coordination and gait, and are unfortunately fatal in nature, with the exception of SCA6. All the polyQ spinocerebellar ataxias have a hallmark feature of neuronal aggregations and share many common pathogenic mechanisms, such as mitochondrial dysfunction, impaired proteasomal function, and autophagy impairment. Currently, therapeutic options are limited, with no available treatments that slow or halt disease progression. Here, we discuss the common molecular and clinical presentations of polyQ spinocerebellar ataxias. We will also discuss the promising antisense oligonucleotide therapeutics being developed as treatments for these devastating diseases. With recent advancements and therapeutic approvals of various antisense therapies, it is envisioned that some of the studies reviewed may progress into clinical trials and beyond.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines9111499