PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease

Areum Jo, Yunjong Lee, Tae In Kam, Sung Ung Kang, Stewart Neifert, Senthilkumar S. Karuppagounder, Rin Khang, Hojin Kang, Hyejin Park, Shih Ching Chou, Sungtaek Oh, Haisong Jiang, Deborah A. Swing, Sangwoo Ham, Sheila Pirooznia, George K.E. Umanah, Xiaobo Mao, Manoj Kumar, Han Seok Ko, Ho Chul KangByoung Dae Lee, Yun Il Lee, Shaida A. Andrabi, Chi Hu Park, Ji Yeong Lee, Hanna Kim, Hyein Kim, Hyojung Kim, Jin Whan Cho, Sun Ha Paek, Chan Hyun Na, Lino Tessarollo, Valina L. Dawson, Ted M. Dawson, Joo Ho Shin

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbereaax8891
JournalScience translational medicine
Volume13
Issue number604
DOIs
StatePublished - Jul 28 2021

ASJC Scopus subject areas

  • Medicine(all)

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