Regional transcriptional architecture of Parkinson's disease pathogenesis and network spread
Regional transcriptional architecture of Parkinson's disease pathogenesis and network spread
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DOI：
10.1093/brain/awz223
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发表时间：
2019-10-01
期刊：
影响因子：
14.5
通讯作者：
Raj, Ashish
中科院分区：
文献类型：
--
作者：
Freeze, Benjamin;Pandya, Sneha;Raj, Ashish
虽然已经很好地描述了发生散发性帕金森病的风险的显著遗传贡献，但是在人类中，局部遗传因素、发病机制和随后的病理在整个大脑中的传播之间的关系在很大程度上是无法解释的。为了解决这个问题，我们使用网络扩散模型来推断可能的病理种子区域和疾病传播的模式，从MRI萎缩图来自帕金森氏病进展标志物倡议研究中的232个从头受试者。艾伦脑图谱区域转录谱的67个帕金森病的危险因素基因被映射到推断的种子区域，以确定遗传危险因素的局部影响。我们使用层次聚类和L-1正则化回归分析表明，免疫相关和溶酶体风险因子基因的转录谱预测种子区域的位置和疾病传播的模式，从最有可能的种子区域，黑质。通过利用转录组学的最新进展，我们表明，通过高保真度基因表达量化的区域小胶质细胞丰度也预测了种子区域的位置。这些发现表明，早期疾病部位在遗传上易受溶酶体α-突触核蛋白加工功能障碍和小胶质细胞介导的神经炎症的影响，这可能启动疾病过程并导致病理学沿沿着神经连接通路传播。
Although a significant genetic contribution to the risk of developing sporadic Parkinson's disease has been well described, the relationship between local genetic factors, pathogenesis, and subsequent spread of pathology throughout the brain has been largely unexplained in humans. To address this question, we use network diffusion modelling to infer probable pathology seed regions and patterns of disease spread from MRI atrophy maps derived from 232 de novo subjects in the Parkinson's Progression Markers Initiative study. Allen Brain Atlas regional transcriptional profiles of 67 Parkinson's disease risk factor genes were mapped to the inferred seed regions to determine the local influence of genetic risk factors. We used hierarchical clustering and L-1 regularized regression analysis to show that transcriptional profiles of immune-related and lysosomal risk factor genes predict seed region location and the pattern of disease propagation from the most likely seed region, substantia nigra. By leveraging recent advances in transcriptomics, we show that regional microglial abundance quantified by high fidelity gene expression also predicts seed region location. These findings suggest that early disease sites are genetically susceptible to dysfunctional lysosomal alpha-synuclein processing and microglia-mediated neuroinflammation, which may initiate the disease process and contribute to spread of pathology along neural connectivity pathways.