Abstract
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.
Highlights
Spinocerebellar ataxias (SCAs) are neurodegenerative diseases that cause progressive loss of cerebellar neurons and connected regions of the nervous system, resulting in unsteady gait, clumsiness, and dysarthria (Buijsen et al, 2019)
What is often observed within the subtype, is the fact that toxic polyQ proteins generated from abnormal CAG repeat expansion lead to their nuclear
We have reviewed current updates on the cell biological mechanisms underpinning the polyQ expansion and nuclear accumulation of disease-associated polyQ SCA proteins
Summary
Spinocerebellar ataxias (SCAs) are neurodegenerative diseases that cause progressive loss of cerebellar neurons and connected regions of the nervous system, resulting in unsteady gait, clumsiness, and dysarthria (Buijsen et al, 2019). In a subset of polyQ SCA diseases (SCA3, SCA6, and SCA7), polyQ-expanded SCA proteins abnormally translocate from their original locations, such as the cytoplasm or cytoplasmic membrane, into the nucleus upon polyQ SCA-associated genetic mutations (Havel et al, 2009) These nuclear polyQ SCA proteins sequester other nuclear proteins, primarily including transcription factors (TFs), thereby disrupting gene transcription. A genome-wide association study revealed that genes associated with mismatch repair, including MSH3, MLH1, and PMS1, modify age of onset for HD (Genetic Modifiers of Huntington’s Disease Consortium, 2019) These findings suggest that common DNA repair pathways influence TNR expansion (Jones et al, 2017; Massey and Jones, 2018; Yau et al, 2018). Given that TC-NER and mismatch repair pathways are regulated through separate routes (Hakem, 2008; Massey and Jones, 2018), the TABLE 1 | A list of polyQ SCAs with a brief description of each disease
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