Function and Dysfunction of LRRK2

LRRK2 的功能和功能障碍

基本信息

批准号：
8451474
负责人：
Jie Shen
金额：
$ 36.05万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451474
关键词：
Acute Affect Alleles Amino Acid Substitution Amphetamines Apoptotic Behavioral Paradigm Bradykinesia Brain Breeding Calcium Catecholamines Cell Death Cells Chromaffin Cells Clinical Cognitive Corpus striatum structure Cytosol Defect Degradation Pathway Development Dopamine Dopamine D2 Receptor Employee Strikes Endoplasmic Reticulum Event Exhibits Exocytosis Family Functional disorder Generations Genes Genetic Goals Guanosine Triphosphate Phosphohydrolases High Pressure Liquid Chromatography Homologous Gene Image Impairment In Situ Hybridization Inflammatory Response Kidney Knock-out Knockout Mice LRRK2 gene Levodopa Life Link Measures Mediating Microdialysis Midbrain structure Mitochondria Molecular Movement Disorders Mus Mutation Neurodegenerative Disorders Neurons Organ PINK1 gene Parkin gene Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Pattern Pharmaceutical Preparations Phenotype Physiological Play Production Prosencephalon Proteins Regulation Rest Tremor Role Slice Substantia nigra structure Syndrome System Work age related alpha synuclein calmodulin-dependent protein kinase II cell type conditioned fear dopaminergic neuron genetic analysis hippocampal pyramidal neuron in vivo insight multidisciplinary neurotransmission new therapeutic target oxidative damage parkin gene/protein protein degradation public health relevance reuptake synuclein

项目摘要

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.

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，其特征为静止性震颤、强直和运动迟缓。这些临床特征被认为是由于纹状体的多巴胺能输入减少引起的，这是由黑质中的多巴胺能神经元退化引起的。 PD 的发生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 个不同基因（a-突触核蛋白、parkin、DJ-1、PINK1 和 LRRK2）的突变有关。阐明家族性帕金森病选择性多巴胺能变性的致病机制可能会为特发性帕金森病的致病机制提供重要线索。 LRRK2 突变是晚发性 PD 最常见的遗传原因，但哺乳动物 LRRK2 的正常生理作用尚不清楚。有趣的是，在高度保守的 GTPase 结构域中的同一 R1441 残基上发现了多个氨基酸取代（R1441C、R1441G 和 R1441H），突出了该残基在 PD 发病机制中的重要性。我们对 LRRK2 敲入 (KI) 小鼠的一代和多学科分析表明，R1441C 突变会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，我们提出以下两个具体目标，以揭示LRRK2在小鼠中的正常生理作用，并研究LRRK2突变导致PD的致病机制。首先，我们将确定LRRK2在体内的正常生理作用。其次，我们将确定 LRRK2 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，致病性帕金森病突变改变了帕金森病基因产物的正常功能并引起多巴胺能功能障碍，这在帕金森病发病机制中发挥着核心作用，最终导致其退化和帕金森表型的产生。该研究的完成将揭示 LRRK2 的正常生理作用，并为 LRRK2 致病性突变如何导致 PD 提供机制见解。我们的长期目标是了解多巴胺能功能障碍和变性的致病机制，并确定导致 PD 发病机制的细胞和分子途径。