Abstract
Background Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine domains [1]. Aggregation of the different polyglutamine (polyQ) expanded disease proteins have been linked to the toxicity in these disorders [1]. We and others have shown that polyQ expanded proteins can be degraded by autophagy [2], and pharmacological activation of this pathway has hence been suggested as a therapeutic approach for these disorders. However, lately increasing evidence indicating that autophagy dysfunction occurs in several neurodegenerative disorders has emerged and raised concerns regarding using stimulation of this pathway as a therapeutic approach [3]. The aim of this study was to determine if and by which molecular mechanism(s) the expanded SCA7 disease protein ataxin-7 (ATXN7) affects the autophagic process.
Highlights
Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine domains [1]
We have identified a novel p53-mediated mechanism by which aggregating polyQ disease proteins can disrupts autophagic activity and showed that this inhibition contributes to polyQ toxicity
An increased understanding of the molecular mechanism by which autophagy inhibition occurs in neurodegenerative disease is of importance if safe and efficient therapeutic approaches based on autophagy stimulation should be developed
Summary
Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine domains [1]. Conclusions We have identified a novel p53-mediated mechanism by which aggregating polyQ disease proteins can disrupts autophagic activity and showed that this inhibition contributes to polyQ toxicity.
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