PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease
| Autor: | Tae In Kam, Areum Jo, Sungtaek Oh, Yunjong Lee, Sung Ung Kang, Shaida A. Andrabi, Byoung Dae Lee, Ho Chul Kang, Haisong Jiang, Hojin Kang, Lino Tessarollo, Chan Hyun Na, Yun Il Lee, Senthilkumar S. Karuppagounder, Deborah A. Swing, Manoj Kumar, George K.E. Umanah, Xiaobo Mao, Chi Hu Park, Ted M. Dawson, Jin Whan Cho, Hyo Jung Kim, Sangwoo Ham, Han Seok Ko, Hyein Kim, Ji-Yeong Lee, Sheila K. Pirooznia, Joo Ho Shin, Valina L. Dawson, Shih Ching Chou, Hanna Kim, Sun Ha Paek, Stewart Neifert, Hyejin Park, Rin Khang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Parkinson's disease Dopamine Substantia nigra Pharmacology Parkin Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Prenylation medicine Animals Psychological repression Neurodegeneration Parkinson Disease General Medicine Farnesol medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha nervous system diseases Repressor Proteins Substantia Nigra 030104 developmental biology chemistry lipids (amino acids peptides and proteins) 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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