Parkinson's Disease Mouse Model with Mutant LRRK2

描述（申请人提供）：帕金森病是一种常见的神经退行性疾病，伴有明显的功能障碍，由黑质和其他大脑区域的神经变性引起。LRRK2突变是人类帕金森病最常见的已知原因，在某些人群中占帕金森病的20%。最常见的突变是G2019S，在欧洲和北美人群中，高达1%的明显散发的PD中存在，并导致典型的晚发性PD，对左旋多巴有反应，并伴有路易体病理。我们之前报道过突变体LRRK2的表达会在细胞培养中引起实质性的细胞毒性，我们最近发现毒性是通过突变体LRRK2的激酶活性介导的。我们现在建议研究表达G2019S突变的全长人LRRK2或野生型的小鼠模型。我们已经培育出在朊病毒启动子控制下表达LRRK2的转基因小鼠，表型适中，最近又培育出表达水平较高、发育正常的纯合子小鼠。在Specific Aim 1中，我们将描述表达突变体G2019S LRRK2的纯合子转基因小鼠的生存和行为，并在适当的细胞群体中对神经元损失和路易小体或其他pd样神经病理进行初步评估。在特异性目标2中，我们将使用TH启动子将表达α -突触核蛋白截断片段的杂合小鼠与小鼠杂交。一种新的PD模型再现了人类疾病中所见的表型方面，这将是非常有益的。未来对激酶活性作用的研究将阐明其发病机制。此外，LRRK2激酶可能是一个很好的治疗靶点，小鼠模型对临床前治疗试验有价值。

DESCRIPTION (provided by applicant): Parkinson's disease is a common neurodegenerative disease accompanied by significant functional disability, resulting from neurodegeneration in the substantia nigra and other brain regions. LRRK2 mutations constitute the most common identified cause of human PD, accounting for up to 20% of PD in some populations. The most common mutation, G2019S, is present in up to one percent of apparently sporadic PD in European and North American populations, and causes typical late onset PD, with response to L-DOPA, and Lewy body pathology. We have previously reported that expression of mutant LRRK2 causes substantial cell toxicity in cell culture, and we have recently found that toxicity is mediated via kinase activity of mutant LRRK2. We now propose to study mouse models expressing either full-length human LRRK2 with the G2019S mutation or wild-type. We have generated transgenic mice expressing LRRK2 under the control of the prion promoter, which have a moderate phenotype, and we have more recently generated homozygous mice with higher expression levels and normal development. In Specific Aim 1 we will characterize survival and behavior of the homozygous transgenic mice expressing mutant G2019S LRRK2, and perform an initial assessment of neuronal loss and Lewy bodies, or other PD-like neuropathology in appropriate cellular populations. In Specific Aim 2 we will cross the heterozygous mice with mice expressing a truncated fragment of alpha-synuclein using the TH promoter. A new model of PD which reproduces aspects of phenotypes seen in the human disease would be of great benefit. Future studies of the role of kinase activity could clarify pathogenesis. Furthermore LRRK2 kinase may be an excellent therapeutic target, and mouse models would be valuable for preclinical therapeutic trials. PUBLIC HEALTH RELEVANCE: We propose to generate new mouse models of Parkinson's disease. LRRK2 mutations constitute the most common identified cause of human PD, accounting for up to 20% of PD in some populations. We have previously reported that expression of mutant LRRK2 causes substantial cell toxicity in cell culture, and we have recently found that toxicity is mediated via kinase activity of mutant LRRK2. A new mouse model of PD which reproduces aspects of phenotypes seen in the human disease would be of great benefit. Future studies of the role of kinase activity could clarify pathogenesis. Furthermore LRRK2 kinase may be an excellent therapeutic target, and mouse models would be valuable for preclinical therapeutic trials.