Hernandez Dena G, Reed Xylena, Singleton Andrew B
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.
German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Tübingen, Germany.
J Neurochem. 2016 Oct;139 Suppl 1(Suppl 1):59-74. doi: 10.1111/jnc.13593. Epub 2016 Apr 18.
Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.
帕金森病是一种常见的、进行性神经退行性疾病，影响着3%的75岁以上人群。临床上，帕金森病（PD）与静止性震颤、姿势不稳、僵硬、运动迟缓以及对左旋多巴治疗反应良好有关。在过去15年里，大量研究证实遗传因素在PD复杂的发病机制中起作用。在诸如SNCA、Parkin、DJ-1、PINK 1、LRRK2和VPS35等单个基因中发现了产生罕见单基因形式疾病的高外显率突变。LRRK2和GBA中具有不完全外显率的独特变异已被证明在某些人群中是PD的强风险因素。此外，现在已认识到超过20个效应大小较小的常见变异可调节PD风险。对孟德尔形式的PD进行研究为更常见的特发性疾病形式的病理生理学提供了宝贵的见解；然而，尚未开发出治疗方法。此外，对于已确定的常见风险等位基因，风险背后的功能基础主要仍不清楚。未来十年的挑战将是通过评估风险变异的直接生物学后果以及其他高内涵、综合数据集来加强通过基因发现获得的结果。本综述讨论帕金森病的单基因风险因素和孟德尔遗传机制。SNCA、Parkin、DJ-1、PINK 1、LRRK2和VPS35中的高外显率突变产生罕见的单基因形式疾病，而LRRK2和GBA中的独特变异显示不完全外显率，是PD的强风险因素。此外，超过20个效应大小较小的常见变异调节疾病风险。未来十年的挑战是通过评估风险变异的直接生物学后果以及高内涵、综合数据集来加强基因研究结果。本文是关于帕金森病的特刊的一部分。
