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

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-soverexpressing 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 promotes GBP2 geranylgeranylation, driving its mitochondrial accumulation. At mitochondria, GBP2 directly binds the mitophagy receptor NIX via its large GTPase domain and targets it for ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy. Accordingly, GBP2 knockdown enhanced mitophagy, improved mitochondrial homeostasis, and protected against neuronal apoptosis. The neuroprotective effects of GBP2 knockdown were abolished by either pharmacological inhibition of mitophagy or genetic knockdown of NIX, indicating a linear pathway. Importantly, therapeutically targeting geranylgeranylation with GGTI298 significantly attenuated MPTP-induced neurotoxicity. Our study unveils a novel, druggable axis in PD pathogenesis where GBP2 disrupts mitochondrial quality control. Targeting GBP2 geranylgeranylation with GGTI298 presents a promising therapeutic strategy. • GBP2 upregulation in PD models exacerbates neurotoxicity and motor deficits. • GBP2 accumulates in mitochondria, where it exacerbates mitochondrial dysfunction upon MPP + stress. • GBP2 binds to the mitophagy receptor NIX via its GTPase domain and promotes its ubiquitination, thereby facilitating NIX degradation and ultimately suppressing mitophagy. • Geranylgeranylation is essential for targeting GBP2 to mitochondria, and its pharmacological inhibition by GGTI298 alleviates PD pathology.