Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands.
Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.
Commun Biol. 2020 Mar 5;3(1):101. doi: 10.1038/s42003-020-0804-9.
The molecular mechanisms underlying caudal-to-rostral progression of Lewy body pathology in Parkinson's disease remain poorly understood. Here, we identified transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological adults from the Allen Human Brain Atlas. Among the genes that are indicative of regional vulnerability, we found known genetic risk factors for Parkinson's disease: SCARB2, ELOVL7, SH3GL2, SNCA, BAP1, and ZNF184. Results were confirmed in two datasets of non-neurological subjects, while in two datasets of Parkinson's disease patients we found altered expression patterns. Co-expression analysis across vulnerable regions identified a module enriched for genes associated with dopamine synthesis and microglia, and another module related to the immune system, blood-oxygen transport, and endothelial cells. Both were highly expressed in regions involved in the preclinical stages of the disease. Finally, alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in Parkinson's disease brains.
帕金森病路易体病理从头至尾进展的分子机制仍知之甚少。在这里，我们从艾伦人类大脑图谱中鉴定了非神经成年人参与 Braak 路易体阶段的大脑区域的转录组特征。在提示区域易损性的基因中，我们发现了帕金森病的已知遗传风险因素：SCARB2、ELOVL7、SH3GL2、SNCA、BAP1 和 ZNF184。结果在两个非神经科受试者数据集得到了证实，而在两个帕金森病患者数据集则发现了改变的表达模式。跨易损区域的共表达分析鉴定了一个富含与多巴胺合成和小胶质细胞相关基因的模块，以及另一个与免疫系统、血氧转运和内皮细胞相关的模块。这两个模块在疾病的临床前阶段所涉及的区域中均高度表达。最后，这些区域特异性功能相关基因的改变可能导致帕金森病大脑的选择性区域易损性。
