Leucine 7 is a key residue for mutant huntingtin-induced mitochondrial pathology and neurotoxicity in Huntington's disease.

ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Mutant huntingtin (mHTT) associates with mitochondria, resulting in mitochondrial dysfunction and neuronal cell death. However, the underlying molecular mechanisms remain unknown. In this study, we investigate the role of N-terminal first 17 amino acids (N17) of mHTT in regulating its mitochondrial localization. Specifically, we demonstrate that the mutation at leucine 7 of N17 domain suppresses the association of mHTT with mitochondria. Blocking mitochondrial localization of HTT exon 1 with 73 glutamine repeats (HTT-Q73) strongly ameliorates polyglutamine-induced reduction of mitochondrial membrane potential, increase of reactive oxygen species production, a

SUBMITTER: Zhang S 

PROVIDER: S-EPMC11930128 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature