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Citation
Sun, L., Zhang, J., Chen, W., Chen, Y., Zhang, X., Yang, M., Xiao, M., Ma, F., Yao, Y., Ye, M., Zhang, Z., Chen, K., Chen, F., Ren, Y., Ni, S., Zhang, X., Yan, Z., Sun, Z.R., Zhou, H.M., Yang, H., Xie, S., Haque, M.E., Huang, K., Yang, Y. (2020). Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration.  Aging Cell 19(9): e13210.
FlyBase ID
FBrf0247457
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC7511865 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Aging Cell
    Title
    Aging Cell
    Publication Year
    2002-
    ISBN/ISSN
    1474-9718 1474-9728
    Data From Reference