[Research Articles] PARIS farnesylation prevents neurodegeneration in models of Parkinsons disease
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- 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.
Source: Science Translational Medicine - Category: Biomedical Science Authors: Jo, A., Lee, Y., Kam, T.-I., Kang, S.-U., Neifert, S., Karuppagounder, S. S., Khang, R., Kang, H., Park, H., Chou, S.-C., Oh, S., Jiang, H., Swing, D. A., Ham, S., Pirooznia, S., Umanah, G. K. E., Mao, X., Kumar, M., Ko, H. S., Kang, H. C., Lee, B. D., Le Tags: Research Articles Source Type: research