Farnesylation of Paris prevents neurodegeneration in a model of Parkinson's disease

DOI: 10.1126 / scitranslmed.aax8891

Commentary

In this study, the accumulation of parkin-interacting substrate (PARIS; ZNF746) due to parkin inactivation contributes to Parkinson's disease (PD) through the inhibition of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; PPARGC1A) activity, and therefore, farnesol was used as an inhibitor of PARIS This is what identifies farnesol as an inhibitor of PARIS.

Farnesol has been shown to prevent inhibition of PGC-1α by promoting farnesylation of PARIS and decreasing its occupancy

Farnesol prevented loss of dopaminergic neurons and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditioned Parkin KO mice, and α-synuclein preformed fibril model of sporadic PD.

Farnesylation of PARIS is reduced in the substantia nigra of PD patients, suggesting that reduced farnesylation of PARIS may be involved in PD, and therefore farnesol may be beneficial in the treatment of PD by enhancing PARIS farnesylation and restoring PGC-1α activity.