巴黎法呢基化可预防帕金森病模型中的神经退行性变。
PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease.
机构信息
Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Sci Transl Med. 2021 Jul 28;13(604). doi: 10.1126/scitranslmed.aax8891.
Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; ) 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 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.
由于 parkin 的失活导致 parkin 相互作用底物 (PARIS; ) 的积累，通过抑制过氧化物酶体增殖物激活受体-γ 共激活因子-1α (PGC-1α; ) 的活性，导致帕金森病 (PD)。在这里，我们确定法尼醇是 PARIS 的抑制剂。法尼醇促进 PARIS 的法尼基化，通过减少 PARIS 在 启动子上的占据来防止其对 PGC-1α 的抑制。法尼醇通过 PARIS 在 PARIS 转基因小鼠、腹侧中脑 AAV-PARIS 转导、成年条件性 parkin KO 小鼠和散发性 PD 的 α-突触核蛋白原纤维模型中的法尼基化，防止多巴胺能神经元丢失和行为缺陷。PD 患者黑质中的 PARIS 法尼基化减少，提示 PARIS 的法尼基化减少可能在 PD 中起作用。因此，法尼醇通过增强 PARIS 的法尼基化和恢复 PGC-1α 的活性，可能有益于 PD 的治疗。
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