Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy.

ABSTRACT: Parkinson's disease (PD), characterized by dopaminergic neuron loss, still lacks disease-modifying therapies due to incompletely understood mechanisms. Guanylate-binding proteins (GBPs) are well-known immune regulators, but their roles in PD are largely unknown. In this study, we identify GBP2 as a critical driver of PD pathogenesis by impairing mitophagy. We found that GBP2 was significantly upregulated in the substantia nigra of PD patients, and in both MPTP-induced and A53T transgenic mouse models, as well as in MPP⁺-treated or A53T α-synuclein-overexpressing SH-SY5Y cells. Both in vivo and in vitro, genetic knockdown of GBP2 robustly alleviated the MPTP/MPP⁺-induced motor deficits, dopaminergic neuron loss, and apoptosis. Mechanistically, PD-related stress promote

SUBMITTER: Cui W 

PROVIDER: S-EPMC12859793 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature