BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson's disease.

ABSTRACT: Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function. Our findings reveal a consistent downregulation of BCKDK in dopaminergic (DA) neurons from A53T-αSyn mouse models, PD patient-derived induced pluripotent stem (iPS) cells, and postmortem brain tissues. BCKDK deficienc

SUBMITTER: Jishi A 

PROVIDER: S-EPMC11662730 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature