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

α-突触核蛋白和 LRRK2 在帕金森病发病机制中的作用

• 批准号: 9297399
• 负责人: Jie Shen
• 金额: $ 140.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297399
• 关键词: Address; Affect; Aging; Autophagocytosis; Boston; Bradykinesia; Budgets; Clinical; Communities; Community Outreach; Corpus striatum structure; Cytoplasmic Inclusion; Development Plans; Disease; Dopamine; Foundations; Gaucher Disease; Gene Deletion; Genes; Genetic; Genetic Models; Goals; Homeostasis; Human; Impairment; Individual; LRRK2 gene; Lead; Lewy Bodies; Link; Molecular; Movement Disorders; Mus; Mutagenesis; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; New England; Parkinson Disease; Parkinson' s Disease Pathway; Pathogenesis; Pathogenicity; Pathway interactions; Progressive Disease; Proteins; Regulation; Research; Research Personnel; Research Project Grants; Resources; Rest Tremor; Retreatment; Role; SNCA gene; Substantia nigra structure; Symptoms; Synapses; Time; Training; Treatment Efficacy; Triad Acrylic Resin; age related; alpha synuclein; alpha synuclein gene; base; career; career development; design; dopaminergic neuron; induced pluripotent stem cell; insight; interest; member; neurotoxicity; next generation; nigrostriatal pathway; novel; outreach program; pars compacta; programs; progressive neurodegeneration; protein E; public health relevance; social media; symposium; web site

 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.

 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 的临床三联征为静止性震颤、强直和运动迟缓。 PD 是黑质神经元的进行性变性，并且神经元内细胞质内含物（称为路易体）的存在是 PD 最常见的遗传原因，但这些突变的机制仍不清楚。新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。 α-突触核蛋白是一种底物。该通路的破坏可以解释 PD 中的 DA 神经变性，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，从而导致衰老过程中的神经变性。然而，LRRK2 如何调节自噬以及 PD 突变是否会影响。此外，α-突触核蛋白聚集（PD 的神经病理学标志）在衰老过程中会导致神经退行性变，但其机制仍有待阐明。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由 Südhof 博士指导的研究核心项目 1，旨在阐明 α-突触核蛋白对小鼠和人类的神经毒性机制。项目 2 由 Shen 博士指导，旨在研究 α-突触核蛋白和 LRRK 在调节自噬和多巴胺能神经元存活中的遗传相互作用。由 Yue 博士领导的研究中心提议研究 LRRK 调节自噬和 α-突触核蛋白稳态的分子途径，由 Shen 博士领导的研究核心将通过生成和提供多个至关重要的突变小鼠品系来服务于所有三个项目。行政核心也由沉博士领导，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推广计划，这些高度集成、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见解，并有助于发现可进一步探索和开发为有效的疾病缓解疗法的新途径。