PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease.
Areum JoByoung Dae LeeTae-In KamSung-Ung KangStewart NeifertSenthilkumar S KaruppagounderRin KhangHojin KangHyejin ParkShih-Ching ChouSung-Taek OhHaisong JiangDeborah A SwingSangwoo HamSheila PiroozniaGeorge K E UmanahXiaobo MaoManoj KumarHan Seok KoHo Chul KangByoung Dae LeeYun-Il LeeShaida A AndrabiChi-Hu ParkJi-Yeong LeeHanna KimHyein KimHyo-Jung KimJin Whan ChoSun Ha PaekChan Hyun NaLino TessarolloValina L DawsonTed M DawsonJoo-Ho ShinPublished in: Science translational medicine (2021)
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.