N‐homocysteinylation of DJ‐1 promotes neurodegeneration in Parkinson's disease
Tao Guo, Lingyan Zhou, Min Xiong, Jing Xiong, Juan Huang, Yiming Li, Guoxin Zhang, Guiqin Chen, Zhi‐Hao Wang, Tingting Xiao, Dan Hu, Anyu Bao, Zhentao Zhang
Abstract
DJ-1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ-1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ-1 on the lysine 182 (K182) residue in an age-dependent manner. The N-homocysteinylation (N-hcy) of DJ-1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N-hcy of DJ-1 restores its protective effect. These results indicate that the N-hcy of DJ-1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N-hcy of DJ-1 may exert neuroprotective effect against PD.