PROTAC-Mediated Degradation of mHTT Aggregates Attenuates Neurotoxicity in Cellular and R6/2 Mouse Models of Huntington's Disease.

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in thegene, producing mutant huntingtin (mHTT) that misfolds into β-sheet-rich aggregates and drives neuronal loss. Current HTT-lowering strategies face challenges, including invasive delivery and nonselective suppression of wild-type HTT. Here, we report the development and synthesis of proteolysis-targeting chimeras (PROTACs) to selectively degrade aggregated mHTT. The lead compound, PROTAC, consists of a (pyridylvinyl)aniline aggregate-binding ligand linked via polyethylene glycol spacers to pomalidomide, an E3 ligase recruiter for cereblon. PROTACselectively degraded mHTT aggregates without affecting wild-type huntingtin and significantly reduced mHTT-induced cytotoxicity in the cell model. LC-MS/MS analysis confirmed the blood-brain barrier (BBB) penetration ability of PROTACfollowing subcutaneous administration. In an R6/2 HD mouse model, continuous PROTACdelivery via osmotic pumps improved body weight, motor coordination, and survival, correlating with reduced mHTT aggregation and neuroinflammation in the brain. These results highlight the therapeutic potential of aggregate-selective degradation as a disease-modifying strategy for HD, providing a promising alternative to conventional HTT-lowering approaches and supporting the broader potential of PROTAC-based therapeutics for neurodegenerative proteinopathies.