Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths - PubMed
4 hours ago
- #Huntington's disease
- #polyQ length
- #autophagy
- Huntington's disease (HD) involves mutant huntingtin (mHTT) aggregates with polyglutamine (polyQ) tracts that impair autophagy.
- Different polyQ lengths cause distinct autophagy impairment mechanisms: polyQ103 aggregates evade recognition by autophagy receptor SQSTM1/p62, while polyQ43 condensates are recognized but hinder complete autophagosome formation.
- Overexpression of autophagy receptor optineurin (Optn) binds preferentially to polyQ103 aggregates, improving cell survival; recruitment relies on K63-ubiquitination of aggregates binding to Optn's UBAN domain.
- Findings reveal polyQ length-dependent autophagy impairment, suggesting targeted therapies for longer polyQ sequences in HD.