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表观遗传调节因子 SMARCA4 和 ERK-ETS 信号的衰减抑制与衰老相关的多巴胺能变性。

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

机构信息

Institute of Life Sciences, Fuzhou University, Fuzhou, Fujian, China.

Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN, USA.

出版信息

Aging Cell. 2020 Sep;19(9):e13210. doi: 10.1111/acel.13210. Epub 2020 Aug 4.

DOI:10.1111/acel.13210
PMID:32749068
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7511865/
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.

摘要

遗传、环境因素和衰老的复杂相互作用如何共同导致帕金森病（PD）中的多巴胺能变性在很大程度上尚不清楚。在这里，我们应用人类患者黑质特异性微阵列数据集的频繁基因共表达分析来鉴定潜在的新的疾病相关基因。体内果蝇研究验证了 32 个候选基因中的两个，即染色质重塑因子 SMARCA4 和胆红素还原酶 BLVRA。SMARCA4 的抑制不仅能够预防由 BLVRA 过表达引起的、也能够预防四种最常见的果蝇 PD 模型中与衰老相关的多巴胺能变性。此外，SMARCA4 在多巴胺能神经元中的特异性下调可防止α-突触核蛋白和 LRRK2 引起的寿命缩短。从机制上讲，异常的 SMARCA4 和 BLVRA集中在升高的 ERK-ETS 活性上，通过遗传或药理学操作对其进行抑制可有效抑制体内果蝇的多巴胺能变性。SMARCA4 的下调或 MEK/ERK 的药物抑制也减轻了 PINK1（一种与 PD 相关的基因）缺陷的人类细胞中的线粒体缺陷。我们的研究结果强调了表观遗传调节剂的重要作用，并暗示了一种共同的信号轴，可用于治疗正常衰老和广泛的与年龄相关的疾病，包括 PD。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/b53636f86a9f/ACEL-19-e13210-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/9cab4d19cecb/ACEL-19-e13210-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/f8e3af519d6b/ACEL-19-e13210-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/f6a135c1d84e/ACEL-19-e13210-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/ec3d1aac6c6f/ACEL-19-e13210-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/60e6ab4497aa/ACEL-19-e13210-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/b53636f86a9f/ACEL-19-e13210-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/9cab4d19cecb/ACEL-19-e13210-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/f8e3af519d6b/ACEL-19-e13210-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/f6a135c1d84e/ACEL-19-e13210-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/ec3d1aac6c6f/ACEL-19-e13210-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/60e6ab4497aa/ACEL-19-e13210-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bdc/7511865/b53636f86a9f/ACEL-19-e13210-g006.jpg

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