PT  - JOURNAL ARTICLE
AU  - Ling Sun
AU  - Jie Zhang
AU  - Wenfeng Chen
AU  - Yun Chen
AU  - Xiaohui Zhang
AU  - Mingjuan Yang
AU  - Min Xiao
AU  - Fujun Ma
AU  - Yizhou Yao
AU  - Meina Ye
AU  - Zhenkun Zhang
AU  - Kai Chen
AU  - Fei Chen
AU  - Yujun Ren
AU  - Shiwei Ni
AU  - Xi Zhang
AU  - Zhangming Yan
AU  - Zhi-Rong Sun
AU  - Hai-Meng Zhou
AU  - Hongqin Yang
AU  - Shusen Xie
AU  - M Emdadul Haque
AU  - Kun Huang
AU  - Yufeng Yang
TI  - Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration
AID  - 10.1101/835876
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 835876
4099  - http://biorxiv.org/content/early/2019/11/12/835876.short
4100  - http://biorxiv.org/content/early/2019/11/12/835876.full
AB  - Parkinson’s disease (PD) is a complex disease with high heterogeneity. How complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in 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 dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. 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 vivo. Drug inhibition of MEK/ERK also mitigated mitochondrial defects in PD gene-deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in a broad range of aging-related disorders including PD.PDParkinson’s diseaseSMARCA4SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4BLVRAbiliverdin reductase A