The Mechanisms of Nuclear Proteotoxicity in Polyglutamine Spinocerebellar Ataxias

Polyglutamine (polyQ) spinocerebellar ataxias (SCAs) are the most prevalent subset of SCAs and share the aberrant expansion of Q-encoding CAG repeats within the coding sequences of disease-responsible genes as their common genetic cause. These polyQ SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) are...

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Published inFrontiers in neuroscience Vol. 14; p. 489
Main Authors Lee, Davin, Lee, Yun-Il, Lee, Young-Sam, Lee, Sung Bae
Format Journal Article
LanguageEnglish
Published Lausanne Frontiers Research Foundation 04.06.2020
Frontiers Media S.A
Subjects
Ataxin
Atrophy
CAG repeat expansion
Cell cycle
Cerebellum
Cytoplasm
Deoxyribonucleic acid
Disease
DNA
DNA damage
DNA methylation
DNA repair
Gene expression
Genotype & phenotype
Localization
Mutation
Nervous system
Neural coding
Neurodegenerative diseases
Neuroscience
nuclear proteotoxicity
nuclear translocation
Polyglutamine
polyQ SCAs
Proteins
repeat instability
Risk factors
Signal transduction
Spinocerebellar ataxia
Transcription factors
Trinucleotide repeat diseases
Trinucleotide repeats
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Summary:Polyglutamine (polyQ) spinocerebellar ataxias (SCAs) are the most prevalent subset of SCAs and share the aberrant expansion of Q-encoding CAG repeats within the coding sequences of disease-responsible genes as their common genetic cause. These polyQ SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) are inherited neurodegenerative diseases characterized by the progressive atrophy of the cerebellum and connected regions of the nervous system, which leads to loss of fine muscle movement coordination. Upon the expansion of polyQ repeats, the mutated proteins typically accumulate disproportionately in the neuronal nucleus, where they sequester various target molecules including transcription factors and other nuclear proteins. However, it is not yet clearly understood how CAG repeat expansion takes place or how expanded polyQ proteins accumulate in the nucleus. In this article, we review the current knowledge on the molecular and cellular bases of nuclear proteotoxicity of polyQ proteins in SCAs and present our perspectives on the remaining issues surrounding these diseases.
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Edited by: Doyoun Kim, Korea Research Institute of Chemical Technology (KRICT), South Korea
This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience
Reviewed by: Wei-Ling Tsou, Wayne State University, United States; Hong Jiang, Central South University, China
These authors have contributed equally to this work
ISSN:1662-453X
1662-4548
1662-453X
DOI:10.3389/fnins.2020.00489