Autophagy at the Crossroads of Protein and RNA Toxicity in Repeat Expansion Cerebellar Ataxias
Abstract
Repeat expansion cerebellar ataxias comprise a genetically and mechanistically heterogeneous group of neurodegenerative disorders unified by the pathological expansion of short tandem repeats (STRs) beyond a disease-causing threshold. Depending on their genomic localization, these expansions can lead to toxic protein gain-of-function, as in polyglutamine (polyQ) cerebellar ataxias, or to RNA-mediated toxicity and repeat-associated non-AUG (RAN) translation, for which recent evidence supports a major pathogenic role in non-coding spinocerebellar ataxias (SCAs). Despite these distinct upstream mechanisms, disruption of neuronal homeostasis occurs through converging pathogenic processes, including proteostasis impairment, transcriptional dysregulation, and mitochondrial dysfunction, leading to progressive neuronal loss. Importantly, impaired autophagy has been consistently reported across multiple repeat expansion ataxias, including both dominant SCAs and recessive conditions, such as Friedreich's ataxia, suggesting that impairment of this pathway may represent a shared downstream event in disease progression. Indeed, in polyQ cerebella ataxias, the accumulation of misfolded and aggregation-prone proteins places a substantial burden on cellular quality control systems, particularly the ubiquitin-proteasome system and autophagy. Similarly, in non-coding SCAs, toxic RNA species and RAN-derived peptides might interfere with protein clearance mechanisms and contribute to cellular…
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