Integrated molecular landscape of Parkinson's disease.
Integrated molecular landscape of Parkinson's disease.
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DOI：
10.1038/s41531-017-0015-3
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Poelmans G
中科院分区：
文献类型：
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作者：
Klemann CJHM;Martens GJM;Sharma M;Martens MB;Isacson O;Gasser T;Visser JE;Poelmans G
帕金森氏症是由遗传和环境因素复杂的相互作用引起的。虽然许多独立的分子途径和过程与家族性帕金森病有关，但尤其是散发性帕金森病的共同机制仍很不清楚。为了进一步了解帕金森病的病因，我们在这里进行了遗传网络和文献分析，将13项已发表的关于帕金森病(涉及13.094例病例和47.148名对照)和其他与(家族性)帕金森病有关的基因的全基因组关联研究的顶级发现整合到一个分子相互作用的图景中。帕金森病的分子图景包含四个主要的生物学过程-氧化应激反应、内体-溶酶体功能、内质网应激反应和免疫反应激活-这些过程相互作用，调节多巴胺能神经元的功能和死亡，这是帕金森病的病理特征。有趣的是，脂类和脂蛋白在功能上参与并受所有这些过程的影响，并影响多巴胺能神经元特异性信号级联反应。此外，我们通过全基因组关联研究基于数据的多基因风险评分分析来验证帕金森氏症与脂质的关系，这些分析表明脂质/脂蛋白特征和帕金森病之间存在共同的遗传风险。综上所述，我们的发现为(散发性)帕金森病病因学的分子机制提供了新的见解，并突出了脂类和脂蛋白在帕金森病发病机制中的关键作用，为帕金森病的疾病修饰治疗的发展提供了重要线索。脂类和脂蛋白在帕金森氏病(PD)的四个关键生物学过程中起着核心作用。利用生物信息学和其他对先前发表的数据的广泛分析，荷兰、德国和美国的Geert Poelmann、Cornelius Klemann及其同事绘制了由与家族性和散发性PD相关的基因编码的蛋白质之间的相互作用图。他们认为氧化应激反应、溶酶体功能、内质网应激反应和免疫反应激活是导致多巴胺能神经元死亡的主要机制。脂质信号涉及所有这四个过程，作者发现特定的脂类和脂蛋白水平与帕金森病的风险之间存在联系。这些发现表明，调节脂质或脂蛋白水平的化合物为帕金森病提供了一种潜在的新治疗策略。
Parkinson’s disease is caused by a complex interplay of genetic and environmental factors. Although a number of independent molecular pathways and processes have been associated with familial Parkinson’s disease, a common mechanism underlying especially sporadic Parkinson’s disease is still largely unknown. In order to gain further insight into the etiology of Parkinson’s disease, we here conducted genetic network and literature analyses to integrate the top-ranked findings from thirteen published genome-wide association studies of Parkinson’s disease (involving 13.094 cases and 47.148 controls) and other genes implicated in (familial) Parkinson’s disease, into a molecular interaction landscape. The molecular Parkinson’s disease landscape harbors four main biological processes—oxidative stress response, endosomal-lysosomal functioning, endoplasmic reticulum stress response, and immune response activation—that interact with each other and regulate dopaminergic neuron function and death, the pathological hallmark of Parkinson’s disease. Interestingly, lipids and lipoproteins are functionally involved in and influenced by all these processes, and affect dopaminergic neuron-specific signaling cascades. Furthermore, we validate the Parkinson’s disease -lipid relationship by genome-wide association studies data-based polygenic risk score analyses that indicate a shared genetic risk between lipid/lipoprotein traits and Parkinson’s disease. Taken together, our findings provide novel insights into the molecular pathways underlying the etiology of (sporadic) Parkinson’s disease and highlight a key role for lipids and lipoproteins in Parkinson’s disease pathogenesis, providing important clues for the development of disease-modifying treatments of Parkinson’s disease. Lipids and lipoproteins play a central role in four key biological processes underlying Parkinson’s disease (PD). Using bioinformatics and other extensive analyses of previously published data, Geert Poelmans, Cornelius Klemann and colleagues in The Netherlands, Germany and the USA have mapped the interactions of proteins that are encoded by genes associated with both familial and sporadic forms of PD. They identify the oxidative stress response, lysosomal function, endoplasmic reticulum stress response and immune response activation as the main mechanisms leading to the death of dopaminergic neurons. Lipid signaling is implicated in all four of these processes and the authors find a link between the levels of particular lipids and lipoproteins and the risk of PD. These findings suggest that compounds that regulate lipid or lipoprotein levels offer a potential new treatment strategy for PD.