Wang James K T, Langfelder Peter, Horvath Steve, Palazzolo Michael J
Consultant to CHDI FoundationPrinceton, NJ, USA.
Department of Human Genetics, David Geffen School of Medicine, University of CaliforniaLos Angeles, CA, USA.
Front Neurosci. 2017 Mar 31;11:149. doi: 10.3389/fnins.2017.00149. eCollection 2017.
Huntington's disease (HD) is a progressive and autosomal dominant neurodegeneration caused by CAG expansion in the huntingtin gene (), but the pathophysiological mechanism of mutant HTT (mHTT) remains unclear. To study HD using systems biological methodologies on all published data, we undertook the first comprehensive curation of two key PubMed HD datasets: perturbation genes that impact mHTT-driven endpoints and therefore are putatively linked causally to pathogenic mechanisms, and the protein interactome of HTT that reflects its biology. We perused PubMed articles containing co-citation of gene IDs and MeSH terms of interest to generate mechanistic gene sets for iterative enrichment analyses and rank ordering. The HD Perturbation database of 1,218 genes highly overlaps the HTT Interactome of 1,619 genes, suggesting links between normal HTT biology and mHTT pathology. These two HD datasets are enriched for protein networks of key genes underlying two mechanisms not previously implicated in HD nor in each other: exosome synaptic functions and homeostatic synaptic plasticity. Moreover, proteins, possibly including HTT, and miRNA detected in exosomes from a wide variety of sources also highly overlap the HD datasets, suggesting both mechanistic and biomarker links. Finally, the HTT Interactome highly intersects protein networks of pathogenic genes underlying Parkinson's, Alzheimer's and eight non-HD polyglutamine diseases, ALS, and spinal muscular atrophy. These protein networks in turn highly overlap the exosome and homeostatic synaptic plasticity gene sets. Thus, we hypothesize that HTT and other neurodegeneration pathogenic genes form a large interlocking protein network involved in exosome and homeostatic synaptic functions, particularly where the two mechanisms intersect. Mutant pathogenic proteins cause dysfunctions at distinct points in this network, each altering the two mechanisms in specific fashion that contributes to distinct disease pathologies, depending on the gene mutation and the cellular and biological context. This protein network is rich with drug targets, and exosomes may provide disease biomarkers, thus enabling drug discovery. All the curated datasets are made available for other investigators. Elucidating the roles of pathogenic neurodegeneration genes in exosome and homeostatic synaptic functions may provide a unifying framework for the age-dependent, progressive and tissue selective nature of multiple neurodegenerative diseases.
亨廷顿舞蹈症（HD）是一种由亨廷顿基因（）中CAG重复序列扩增引起的进行性常染色体显性神经退行性疾病，但突变型亨廷顿蛋白（mHTT）的病理生理机制仍不清楚。为了利用系统生物学方法对所有已发表的数据进行HD研究，我们对两个关键的PubMed HD数据集进行了首次全面整理：影响mHTT驱动终点且因此可能与致病机制存在因果联系的扰动基因，以及反映其生物学特性的HTT蛋白相互作用组。我们研读了包含感兴趣的基因ID和医学主题词共同引用的PubMed文章，以生成用于迭代富集分析和排序的机制基因集。1218个基因的HD扰动数据库与1619个基因的HTT相互作用组高度重叠，这表明正常HTT生物学与mHTT病理学之间存在联系。这两个HD数据集富含两种机制的关键基因的蛋白质网络，这两种机制以前在HD中均未涉及，彼此之间也没有关联：外泌体突触功能和稳态突触可塑性。此外，在来自多种来源的外泌体中检测到的蛋白质（可能包括HTT）和miRNA也与HD数据集高度重叠，这表明存在机制和生物标志物方面的联系。最后，HTT相互作用组与帕金森病、阿尔茨海默病以及八种非HD多聚谷氨酰胺疾病、肌萎缩侧索硬化症和脊髓性肌萎缩症的致病基因的蛋白质网络高度相交。这些蛋白质网络又与外泌体和稳态突触可塑性基因集高度重叠。因此，我们假设HTT和其他神经退行性疾病致病基因形成一个庞大的相互关联的蛋白质网络，参与外泌体和稳态突触功能，特别是在这两种机制相交的地方。突变致病蛋白在这个网络的不同点导致功能障碍，每种功能障碍都以特定方式改变这两种机制，这取决于基因突变以及细胞和生物学背景，从而导致不同的疾病病理。这个蛋白质网络富含药物靶点，外泌体可能提供疾病生物标志物，从而有助于药物研发。所有整理后的数据集可供其他研究人员使用。阐明致病神经退行性疾病基因在外泌体和稳态突触功能中的作用，可能为多种神经退行性疾病的年龄依赖性、进行性和组织选择性本质提供一个统一的框架。
