Open AccessAttenuation of epigenetic regulator SMARCA4 and ERK‐ETS signaling suppresses aging‐related dopaminergic degeneration
Author(s) -
Sun Ling,
Zhang Jie,
Chen Wenfeng,
Chen Yun,
Zhang Xiaohui,
Yang Mingjuan,
Xiao Min,
Ma Fujun,
Yao Yizhou,
Ye Meina,
Zhang Zhenkun,
Chen Kai,
Chen Fei,
Ren Yujun,
Ni Shiwei,
Zhang Xi,
Yan Zhangming,
Sun ZhiRong,
Zhou HaiMeng,
Yang Hongqin,
Xie Shusen,
Haque M. Emdadul,
Huang Kun,
Yang Yufeng
Publication year - 2020
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13210
Subject(s) - biology , dopaminergic , substantia nigra , epigenetics , lrrk2 , mapk/erk pathway , neuroscience , microbiology and biotechnology , genetics , dopamine , signal transduction , gene , mutation
Abstract How complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in Parkinson's disease (PD) is largely unclear. Here, we applied frequent gene co‐expression analysis on human patient substantia nigra ‐specific microarray datasets to identify potential novel disease‐related genes. In vivo Drosophila studies validated two of 32 candidate genes, a chromatin‐remodeling factor SMARCA4 and a biliverdin reductase BLVRA. Inhibition of SMARCA4 was able to prevent aging‐dependent dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. Furthermore, down‐regulation of SMARCA4 specifically in the dopaminergic neurons prevented shortening of life span caused by α‐synuclein and LRRK2. Mechanistically, aberrant SMARCA4 and BLVRA converged on elevated ERK‐ETS activity, attenuation of which by either genetic or pharmacological manipulation effectively suppressed dopaminergic degeneration in Drosophila in vivo. Down‐regulation of SMARCA4 or drug inhibition of MEK/ERK also mitigated mitochondrial defects in PINK1 (a PD‐associated gene)‐deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in normal aging and a broad range of age‐related disorders including PD.