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.

parkin 相互作用底物 (PARIS；ZNF746 ) 的积累，由于 parkin 失活，通过抑制过氧化物酶体增殖物激活受体-γ 辅激活因子-1α (PGC-1α；PPARGC1A) 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。Farnesol 促进 PARIS 的法呢基化，通过减少 PARIS 对PPARGC1A 的占用来防止其对 PGC-1α 的抑制发起人。法尼醇通过 PARIS 转基因小鼠中 PARIS 的法尼基化、AAV-PARIS 腹侧中脑转导、成年条件性帕金病 KO 小鼠和散发性 PD 的 α-突触核蛋白预形成原纤维模型来预防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，表明 PARIS 法尼基化减少可能在 PD 中发挥作用。因此，法尼醇可能通过增强 PARIS 的法尼基化和恢复 PGC-1α 活性而有益于 PD 的治疗。