@article{5894397ff95644d085bdcc37535634cb,
title = "Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration",
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.",
keywords = "Drosophila, MAPK-ERK-ETS signaling, Parkinson's disease, SMARCA4/Brahma, aging, neurodegeneration",
author = "Ling Sun and Jie Zhang and Wenfeng Chen and Yun Chen and Xiaohui Zhang and Mingjuan Yang and Min Xiao and Fujun Ma and Yizhou Yao and Meina Ye and Zhenkun Zhang and Kai Chen and Fei Chen and Yujun Ren and Shiwei Ni and Xi Zhang and Zhangming Yan and Sun, {Zhi Rong} and Zhou, {Hai Meng} and Hongqin Yang and Shusen Xie and Haque, {M. Emdadul} and Kun Huang and Yufeng Yang",
note = "Funding Information: We thank Mu‐ming Poo, Bingwei Lu, and Yu Cai for critical comments on the manuscript. We also would like to thank Bingwei Lu, Nancy Bonini, Helena E. Richardson, and Jongkyeong Chung for sharing key fly strains, Wei Wu at Core Facility of Resource and Technology, SIBCB, CAS for providing fly service and fly stocks, and Tsinghua Resource Center for providing fly stocks. This work was supported in part by the National Natural Science Foundation of China (No. 31071296 and 31771410), National Key Basic Research Program of China (973 project, No. 2015CB352006), Province Min‐River Scholar Grant (No. XRC‐0947), the National Natural Science Foundation of China (No. 31070877), Startup Funds from Fuzhou University (Grant #XRC‐1465), the National Natural Science Foundation of China (No. 31970461), Fujian Natural Science Foundation (Grant #2016J01158 & 2017J0106), Education and Scientific Research Projects for Young Teachers in Fujian Province (JAT160071), and United Arab Emirates University Research Grant (31M090). Drosophila Drosophila Funding Information: We thank Mu-ming Poo, Bingwei Lu, and Yu Cai for critical comments on the manuscript. We also would like to thank Bingwei Lu, Nancy Bonini, Helena E. Richardson, and Jongkyeong Chung for sharing key fly strains, Wei Wu at Core Facility of Drosophila Resource and Technology, SIBCB, CAS for providing fly service and fly stocks, and Tsinghua Drosophila Resource Center for providing fly stocks. This work was supported in part by the National Natural Science Foundation of China (No. 31071296 and 31771410), National Key Basic Research Program of China (973 project, No. 2015CB352006), Province Min-River Scholar Grant (No. XRC-0947), the National Natural Science Foundation of China (No. 31070877), Startup Funds from Fuzhou University (Grant #XRC-1465), the National Natural Science Foundation of China (No. 31970461), Fujian Natural Science Foundation (Grant #2016J01158 & 2017J0106), Education and Scientific Research Projects for Young Teachers in Fujian Province (JAT160071), and United Arab Emirates University Research Grant (31M090). Publisher Copyright: {\textcopyright} 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd",
year = "2020",
month = sep,
day = "1",
doi = "10.1111/acel.13210",
language = "English",
volume = "19",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "9",
}