PARIS farnesylation prevents neurodegeneration in models of Parkinson’s disease

Abstract

Farnesol enhances the amounts of farnesylated PARIS and PGC-1α, preventing dopaminergic neuronal loss in Parkinson’s disease models. Destination: PARIS Inactivating Parkin mutations lead to parkin-interacting substrate (PARIS) accumulation and subsequent neurodegeneration in Parkinson’s disease (PD). Inhibiting PARIS accumulation might have therapeutic effect. Here, Jo et al. tested this hypothesis in preclinical PD models. The authors showed that farnesol inhibited PARIS by promoting its farnesylation. In vivo, in multiple rodent PD models, farnesol reduced histological and behavioral abnormalities, and PARIS farnesylation was reduced in brain samples from patients with PD, suggesting that promoting PARIS farnesylation might have therapeutic effects in PD. Accumulation of the parkin-interacting substrate (PARIS; ZNF746), due to inactivation of parkin, contributes to Parkinson’s disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; PPARGC1A) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the PPARGC1A promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditional parkin KO mice, and the α-synuclein preformed fibril model of sporadic PD. PARIS farnesylation is decreased in the substantia nigra of patients with PD, suggesting that reduced farnesylation of PARIS may play a role in PD. Thus, farnesol may be beneficial in the treatment of PD by enhancing the farnesylation of PARIS and restoring PGC-1α activity.