Changes in proteasome ub-receptors Rpn10 and Rpn13 affect Htt degradation
Karlijne Geijtenbeek; Sabine Schipper-Krom; Eric Reits
Huntington’s disease (HD) is a neurodegenerative disorder, characterized by a CAG expansion in the huntingtin gene (HTT). This mutation causes a polyglutamine (polyQ) expansion in the mutant huntingtin (mHTT) protein, leading to aggregates and cellular toxicity. Lowering mHtt protein levels via increased proteasomal degradation is a potential strategy to decrease protein accumulation and neurodegeneration. Proteasome complex formation is regulated via various mechanisms, affecting proteasome activity and selectivity in turn. Previously, we have shown that the ubiquitin proteasome system (UPS) remains functional in HD and is able to degrade mHTT. To analyze whether alterations in proteasome complex composition occur during HD progression, we analyzed proteasome complexes of different HD mouse models at different ages and observed loss of the ubiquitin receptors Rpn10 and Rpn13 from the 19S cap during HD progression. To mimic and study the effects of these alterations on mHtt degradation, we silenced these receptors in striatal cells. Interestingly, Rpn10 and Rpn13 knockdown affects mHtt levels via yet undefined mechanisms.