The role of aging in LRRK2-associated Parkinsons disease

描述(申请人提供)：衰老在LRRK2相关帕金森氏病项目摘要中的作用帕金森氏病(PD)被认为是仅次于阿尔茨海默病的第二种最常见的与年龄相关的神经退行性疾病。帕金森病的主要症状是黑质致密部(SNPC)中脑多巴胺(DA)能神经元随着年龄的增长而进行性变性。人们认为，衰老是帕金森病发生发展的最大危险因素。然而，高级衰老对帕金森病的影响尚不清楚，这在很大程度上是因为缺乏一个强大的小鼠衰老模型，该模型显示随着年龄的增长，DA神经元逐渐退化，这与PD的发病机制相似。虽然大多数帕金森病病例是零星的，但在过去十年的研究中发现了一些与家族性帕金森病相关的基因，包括一种新发现的基因，即富含亮氨酸的重复蛋白激酶2(LRRK2)。LRRK2基因突变是帕金森病最常见的遗传原因，LRRK2基因突变是迄今已知的散发性帕金森病中最强的遗传因素。重要的是，LRRK2的外显率随着年龄的增长而大大增加。LRRK2的重要性提示，有必要以LRRK2作为模型来研究正常衰老对帕金森病发病机制的影响。本研究的目的是建立新型、可靠的LRRK2转基因小鼠衰老模型，通过SNPC中DA神经元的进行性丢失来模拟PD的发病机制，并确定衰老在LRRK2相关PD中的作用。我的假设是，正常衰老过程中的特定变化是LRRK2酶活性异常的原因，而LRRK2酶活性的异常反过来又导致LRRK2相关PD的发病机制。为了验证这一假设，我将首先检验LRRK2在黑质纹状体通路中的选择性表达是否会导致DA神经元的进行性退化，以及与衰老相关的细胞和行为缺陷，从而模拟PD的发病机制。我将进一步研究LRRK2小鼠PD衰老模型中与衰老相关的特定变化是否参与了疾病的发病机制。最后，我将确定衰老对LRRK2相关PD中LRRK2酶活性的影响。这项研究将首次建立一个健壮的LRRK2转基因小鼠衰老模型，其DA神经元进行性变性，模拟PD的发病机制。这项研究将直接确定衰老在帕金森病中的作用，并将为了解LRRK2诱导的DA神经毒性的体内机制提供强有力的工具，以及为疾病分析和药物开发提供一个有价值的平台。重要的是，在获奖期间，我将获得广泛的培训，了解帕金森病小鼠衰老模型的建立和特征，衰老研究，蛋白质组学，以及口头陈述技能和科学写作。这次培训将使我能够建立一个成功的实验室，并开始独立的研究生涯。

DESCRIPTION (provided by applicant): The role of aging in LRRK2-associated Parkinson's disease Project Summary Parkinson's disease (PD) is recognized as the second most common age-related neurodegenerative disorder after Alzheimer's disease. The cardinal symptoms of PD are caused by the progressive degeneration of midbrain dopaminergic (DA) neurons with aging in substantia nigra pars compacta (SNpc). It is believed that aging is the greatest risk factor for the development of PD. However, how advanced aging contributes to PD is poorly understood, largely due to the lack of a robust mouse aging model exhibiting progressive degeneration of DA neurons with aging that mimics PD pathogenesis. While the majority of PD cases are sporadic, investigations in the past decade have led to the identification of a number of genes linked to familial forms of PD, including a newly identified gene known as leucine-rich repeat kinase 2 (LRRK2). Mutations in LRRK2 gene are the most frequent genetic causes of PD and LRRK2 is the strongest genetic factor in sporadic PD known to date. Importantly, the penetrance of LRRK2 is greatly increased with age. The importance of LRRK2 suggests that using LRRK2 as a model is warranted in order to study how normal aging contributes to the disease pathogenesis of PD. The proposed project here is aimed to develop novel and robust LRRK2 transgenic mouse aging models with a progressive loss of DA neurons in SNpc to mimic PD pathogenesis, and to determine the role of aging in LRRK2-associated PD. My hypothesis is that specific changes during normal aging are responsible for aberrant LRRK2 enzymatic activities which in turn cause the disease pathogenesis of LRRK2-associated PD. To test this hypothesis, I will first examine whether selective expression of LRRK2 in the nigrostriatal pathway develops progressive DA neuron degeneration and associated cellular and behavioral deficits with aging that mimics PD pathogenesis. I will further examine whether specific aging-related changes contribute to the disease pathogenesis in LRRK2 mouse aging models of PD. Finally, I will determine the effects of aging on LRRK2 enzymatic activities in LRRK2-associated PD. This study will be the first to establish a robust LRRK2 transgenic mouse aging model with progressive degeneration of DA neurons that mimics PD pathogenesis. The study will directly determine the role of aging in PD and will provide robust tools for understanding the mechanisms of LRRK2-induced DA neurotoxicity in vivo, as well as a valuable platform for disease analysis and drug development. Importantly, during the award period, I will obtain extensive training in developing and characterizing mouse aging model of PD, the aging study, proteomics, and as well as oral presentation skills and scientific writing. This training will enabe me to establish a successful laboratory and launch an independent research career.