| Autor: |
Shiwei Ni, Hongqin Yang, Yun Chen, Meina Ye, Yizhou Yao, Ling Sun, Xiaohui Zhang, M. Emdadul Haque, Xi Zhang, Fei Chen, Ma Fujun, Mingjuan Yang, Jie Zhang, Wenfeng Chen, Yujun Ren, Hai-Meng Zhou, Zhenkun Zhang, Shusen Xie, Kai Chen, Zhangming Yan, Yufeng Yang, Min Xiao, Zhi-Rong Sun, Kun Huang |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| DOI: |
10.1101/835876 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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