LRRK in Autophagy Function and Dopaminergic Neuron Survival

描述（由申请人提供）：帕金森病（PD）是一种与年龄相关的神经退行性疾病，其特征为静息性震颤、强直和运动迟缓。这些临床特征被认为是由于纹状体多巴胺能输入减少引起的，这是由黑质多巴胺能神经元变性引起的。LRRK2突变是迟发性PD最常见的遗传原因，但哺乳动物LRRK2的正常生理作用仍有待阐明。我们之前报道过LRRK2失活会导致自噬功能和蛋白质降解途径的年龄依赖性损伤，导致包括α -突触核蛋白在内的蛋白质的显著积累和聚集，以及老年小鼠凋亡细胞死亡、炎症反应和氧化损伤的增加。有趣的是，这些pd样表型在LRRK2-/-肾脏中观察到，但在大脑中没有。由于LRRK2有一个功能同源物LRRK1， LRRK1也是一种含有GTPase和激酶结构域的ROCO蛋白，我们推断LRRK2-/-大脑中缺乏类似表型是由于LRRK1在大脑中的表达相对较高，这可以弥补LRRK2的缺失，而肾脏中表达的LRRK2水平最高。因此，确定这两种LRRKs的缺失是否会导致大脑中年龄依赖性自噬损伤和多巴胺能变性是很重要的。在本研究中，我们提出了两个特定的目的来研究LRRK在调节多巴胺能神经元自噬和年龄依赖性存活中的作用，并探讨LRRK控制自噬功能的分子机制。本研究的完成将进一步加深我们对LRRK2生物学的认识，明确LRRK调控自噬功能的分子机制，并为LRRK2突变的致病机制提供新的思路。所鉴定的LRRK2分子靶点可作为新的治疗靶点或药效学生物标志物。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by resting tremor, rigidity and bradykinesia. These clinical features are thought to arise from reduced dopaminergic input to the striatum, which is caused by the degeneration of dopaminergic neurons in the substantia nigra. Mutations in LRRK2 are the most common genetic cause of late-onset PD, but the normal physiological role of mammalian LRRK2 remains to be elucidated. We previously reported that inactivation of LRRK2 causes age-dependent impairment of autophagy function and protein degradation pathways, leading to striking accumulation and aggregation of proteins including alpha-synuclein and increases of apoptotic cell death, inflammatory responses and oxidative damage in aged mice. Intriguingly, these PD-like phenotypes were observed in the LRRK2-/- kidney but not in the brain. Since LRRK2 has a functional homologue, LRRK1, which is also a ROCO protein containing GTPase and kinase domains, we reasoned that the lack of similar phenotypes in LRRK2-/- brains is due to the relatively high expression of LRRK1 in the brain, which could compensate for the loss of LRRK2, whereas the kidney expresses the highest level of LRRK2. Thus, it is important to determine whether loss of both LRRKs causes age-dependent autophagy impairment and dopaminergic degeneration in the brain. In this application, we propose two Specific Aims to investigate the role of LRRK in the regulation of autophagy and age-dependent survival of dopaminergic neurons, and to explore the molecular mechanisms by which LRRK controls autophagy function. The completion of the proposed studies will further our understanding of LRRK2 biology, define molecular mechanisms by which LRRK regulates autophagy function, and provide insight into the pathogenic mechanism underlying LRRK2 mutations. The identified molecular targets of LRRK2 may be used as novel therapeutic targets or pharmacodynamic biomarkers.