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

 描述（由申请人提供）： 帕金森病（PD）是最常见的运动障碍，影响全球约500万人。PD的特征在于静止性震颤、强直和运动迟缓的临床三联征。神经病理学的特征是 PD是黑质中神经元的进行性变性和存在称为Lewy小体的神经元内胞质内含物。LRRK 2和α-突触核蛋白基因的突变是PD最常见的遗传原因，但这些突变的潜在机制仍不清楚。新出现的实验证据表明，这两个显性PD基因之间有趣的共同致病机制。例如，LRRK 2是自噬-溶酶体途径的重要调节剂，α-突触核蛋白是其底物。这种途径的破坏可以解释PD中的DA神经变性，因为由编码自噬相关蛋白的基因的条件性缺失引起的自噬功能受损导致衰老期间的神经变性。然而，LRRK 2如何调节自噬以及PD突变是否影响其在自噬调节中的作用仍有待阐明。此外，α-突触核蛋白聚集，PD的神经病理学标志，在衰老过程中引起神经退行性变，但其神经毒性的潜在机制需要进一步探索。为了解决这些问题，我们提出了三个相互关联，互补的研究项目和一个研究核心。项目1由Südhof博士指导，旨在阐明小鼠和人类神经元中α-突触核蛋白神经毒性的机制。项目2由沈博士指导，旨在研究α-synuclein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。项目3由Yue博士指导，提出研究LRRK调节自噬和α-突触核蛋白稳态的分子途径。由沈博士指导的研究核心将通过产生和提供三个项目所必需的多个突变小鼠品系来服务于所有三个项目。行政核心，也由沈博士指导，将监督我们的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推广项目。这些高度整合、互补的项目和研究核心的完成将为PD发病机制提供重要的见解，并有助于发现新的途径，这些途径可以进一步探索和开发成有效的疾病修饰疗法。

 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.