In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 13, No. 604 ( 2021-07-28)
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.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.aax8891
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2021
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