The role of aging in LRRK2-associated Parkinsons disease

项目概述帕金森病（PD）是公认的仅次于阿尔茨海默病的第二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中脑多巴胺能（DA）神经元随着衰老而进行性变性。认为衰老是帕金森病发生的最大危险因素。然而，衰老对PD的影响尚不清楚，这主要是因为缺乏一种强大的小鼠衰老模型，该模型显示DA神经元随着衰老而进行性变性，从而模拟PD的发病机制。虽然大多数PD病例是散发性的，但过去十年的研究已经发现了许多与家族性PD相关的基因，包括一种新发现的富含亮氨酸重复激酶2 （LRRK2）基因。LRRK2基因突变是PD最常见的遗传原因，LRRK2是迄今为止已知的散发性PD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的重要性表明，使用LRRK2作为模型是必要的，以研究正常衰老如何促进PD的疾病发病机制。本项目旨在开发新颖且稳健的LRRK2转基因小鼠衰老模型，该模型具有SNpc中DA神经元的进行性丢失，以模拟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导致LRRK2酶活性异常，进而导致LRRK2相关PD的发病机制。为了验证这一假设，我将首先研究LRRK2在黑质纹状体通路中的选择性表达是否会导致进行性DA神经元变性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。我将进一步研究特定的衰老相关变化是否有助于LRRK2小鼠PD衰老模型的疾病发病机制。最后，我将确定衰老对LRRK2相关PD中LRRK2酶活性的影响。本研究将首次建立一种强大的LRRK2转基因小鼠衰老模型，该模型具有模拟PD发病机制的DA神经元进行性变性。该研究将直接确定衰老在PD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大的工具，同时也为疾病分析和药物开发提供了有价值的平台。重要的是，在获奖期间，我将在PD小鼠衰老模型的开发和表征、衰老研究、蛋白质组学以及口头表达能力和科学写作方面得到广泛的训练。这次培训将使我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.