Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration

Ling Sun, Jie Zhang, Wenfeng Chen, Yun Chen, Xiaohui Zhang, Mingjuan Yang, Min Xiao, Fujun Ma, Yizhou Yao, Meina Ye, Zhenkun Zhang, Kai Chen, Fei Chen, Yujun Ren, Shiwei Ni, Xi Zhang, Zhangming Yan, Zhi Rong Sun, Hai Meng Zhou, Hongqin YangShusen Xie, M. Emdadul Haque, Kun Huang, Yufeng Yang

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article numbere13210
JournalAging Cell
Volume19
Issue number9
DOIs
Publication statusPublished - Sep 1 2020

Keywords

  • Drosophila
  • MAPK-ERK-ETS signaling
  • Parkinson's disease
  • SMARCA4/Brahma
  • aging
  • neurodegeneration

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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