alpha-Synuclein and LRRK2 in the Pathogenesis of Parkinson's Disease

 描述(申请人提供)：帕金森氏病(PD)是最常见的运动障碍，全球约有500万人受到影响。帕金森病以静止性震颤、强直、运动迟缓为临床特征。慢性阻塞性肺疾病的神经病理特征 帕金森病是黑质神经元的进行性变性和神经元内存在的被称为路易小体的胞浆内包涵体。LRRK2和α-突触核蛋白基因突变是帕金森病最常见的遗传原因，但这些突变背后的机制仍不清楚。新出现的实验证据表明，这两个显性PD基因之间存在有趣的共同致病机制。例如，LRRK2是自噬-溶酶体途径的重要调节因子，而α-突触核蛋白是该途径的底物。这一通路的中断可能解释了帕金森病患者DA神经退变的原因，因为编码自噬相关蛋白的基因的条件性缺失导致自噬功能受损，导致衰老过程中的神经退变。然而，LRRK2如何调控自噬以及PD突变是否影响其在自噬调控中的作用仍有待阐明。此外，α-突触核蛋白聚集是帕金森病的神经病理标志，可导致衰老过程中的神经退变，但其神经毒性的机制有待进一步探讨。为了解决这些问题，我们提出了三个相互关联、相辅相成的研究项目和一个研究核心。由S博士指导的项目1建议阐明α-突触核蛋白对小鼠和人类神经元的神经毒性机制。项目2由沈博士指导，计划研究α-突触核蛋白和LRRK在自噬和多巴胺能神经元存活调节中的遗传相互作用。由岳博士领导的项目3建议调查LRRK调节自噬和α-突触核蛋白动态平衡的分子途径。由沈博士领导的研究核心将通过培育和提供对这三个项目至关重要的多个突变小鼠品系，为这三个项目提供服务。行政核心，也由沈博士领导，将监督我们尤德尔中心的整体功能和整合，所有项目和核心的科学方向，预算分配， 以及我们广泛的培训和公共宣传计划。这些高度整合、互补的项目和研究核心的完成将为帕金森病的发病机制提供重要的洞察力，并有助于发现可以进一步探索和开发成有效的疾病修改疗法的新途径。

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the most common movement disorder, affecting approximately 5 million people worldwide. PD is characterized by the clinical triad of resting tremor, rigidity and bradykinesia. The neuropathological hallmarks of PD are progressive degeneration of neurons in the substantia nigra and the presence of intraneuronal cytoplasmic inclusions known as Lewy bodies. Mutations in the LRRK2 and α-synuclein genes are the most common genetic cause of PD, but the mechanisms underlying these mutations are still unclear. Emerging experimental evidence suggests intriguing common pathogenic mechanisms between these two dominant PD genes. For example, LRRK2 is an essential regulator of the autophagy-lysosomal pathway, of which α-synuclein is a substrate. Disruption of this pathway may explain DA neurodegeneration in PD, as impaired autophagy function caused by conditional deletion of genes encoding autophagy-related proteins leads to neurodegeneration during aging. However, how LRRK2 regulates autophagy and whether PD mutations affect its role in autophagy regulation remain to be elucidated. Furthermore, α-synuclein aggregation, a neuropathological hallmark of PD, causes neurodegeneration during aging, but the mechanisms underlying its neurotoxicity need to be explored further. To address these questions, we propose three inter-related, complementary Research Projects and one Research Core. Project 1 directed by Dr. Südhof proposes to elucidate the mechanisms of α-synuclein neurotoxicity in mouse and human neurons. Project 2, directed by Dr. Shen, proposes to investigate the genetic interaction between α-synuclein and LRRK in the regulation of autophagy and dopaminergic neuron survival. Project 3, directed by Dr. Yue, proposes to investigate the molecular pathways by which LRRK regulates autophagy and α-synuclein homeostasis. The Research Core, directed by Dr. Shen, will serve all three Projects by generating and providing multiple lines of mutant mice that are essential for the three Projects. The Administrative Core, also directed by Dr. Shen, will oversee the overall function and integration of our Udall Center, scientific directions of all Projects and Core, budget allocation, and our extensive training and public outreach programs. The completion of these highly integrated, complementary Projects and Research Core will provide significant insight into PD pathogenesis, and help uncover novel pathways that can be further explored and developed into effective disease-modifying therapy.