Function and Dysfunction of LRRK2

描述（由申请人提供）：帕金森病（PD）是一种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纹状体多巴胺能输入减少引起的，这是由黑质中多巴胺能神经元的变性引起的。PD的发生在很大程度上是散发性的，但类似散发性PD的临床综合征与至少5种不同基因（α-突触核蛋白、parkin、DJ-1、PINK 1和LRRK 2）的突变有关。阐明家族性PD中选择性多巴胺能变性的致病机制可能为特发性PD的致病机制提供重要线索。LRRK 2的突变是迟发性PD最常见的遗传原因，但哺乳动物LRRK 2的正常生理作用尚不清楚。有趣的是，在高度保守的GT3结构域中的相同R1441残基上已经鉴定出多个氨基酸取代（R1441 C、R1441 G和R1441 H），突出了该残基在PD发病机制中的重要性。我们对LRRK 2敲入（KI）小鼠的一代和多学科分析表明，R1441 C突变损害多巴胺能神经传递和多巴胺D2受体介导的功能。在本申请中，我们提出了以下两个具体目标，以揭示LRRK 2在小鼠中的正常生理作用，并研究LRRK 2突变导致PD的致病机制。首先，我们将确定LRRK 2在体内的正常生理作用。其次，我们将确定LRRK 2突变如何影响多巴胺能神经传递。指导我们建议的中心假设是致病性PD突变改变PD基因产物的正常功能并引起多巴胺能功能障碍，多巴胺能功能障碍在PD发病机制中起核心作用，最终导致其变性和帕金森病表型的产生。这项研究的完成将揭示LRRK 2的正常生理作用，并为LRRK 2致病性突变如何导致PD提供机制性见解。我们的长期目标是了解潜在的多巴胺能功能障碍和变性的致病机制，并表征负责PD发病机制的细胞和分子途径。

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. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD have been linked to mutations in at least 5 distinct genes (a-synuclein, parkin, DJ-1, PINK1 and LRRK2). Elucidation of the pathogenic mechanism underlying the selective dopaminergic degeneration in familial PD will likely provide important clues to the pathogenic mechanism responsible for idiopathic PD. Mutations in LRRK2 are the most common genetic cause of late-onset PD, but the normal physiological role of mammalian LRRK2 is unknown. Interestingly, multiple amino acid substitutions (R1441C, R1441G, and R1441H) have been identified on the same R1441 residue in the highly conserved GTPase domain, highlighting the importance of this residue in PD pathogenesis. Our generation and multidisciplinary analysis of LRRK2 knockin (KI) mice suggests that the R1441C mutation impairs dopaminergic neurotransmission and dopamine D2 receptor-mediated functions. In this application, we propose the following two Specific Aims to uncover the normal physiological role of LRRK2 in mice and to investigate the pathogenic mechanism by which LRRK2 mutations cause PD. First, we will determine the normal physiological role of LRRK2 in vivo. Second, we will determine how LRRK2 mutations affect dopaminergic neurotransmission. The central hypothesis guiding our proposal is that pathogenic PD mutations alter the normal functions of the PD gene products and cause dopaminergic dysfunction, which plays central roles in PD pathogenesis, ultimately leading to their degeneration and production of the parkinsonian phenotypes. The completion of the proposed study will uncover the normal physiological role of LRRK2 and provide mechanistic insight into how LRRK2 pathogenic mutations cause PD. Our long-term goal is to understand the pathogenic mechanism underlying dopaminergic dysfunction and degeneration, and to characterize the cellular and molecular pathways responsible for PD pathogenesis.