Parkinson's Disease Mouse Model with Mutant LRRK2

描述（由申请人提供）：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，由黑质和其他脑区域的神经退行性病变引起。LRRK 2突变是人类PD最常见的已确定原因，在某些人群中占PD的20%。最常见的突变G2019 S存在于欧洲和北美人群中高达1%的明显散发性PD中，并导致典型的迟发性PD，对L-DOPA和路易体病理有反应。我们以前报道过突变体LRRK 2的表达在细胞培养中引起大量的细胞毒性，我们最近发现毒性是通过突变体LRRK 2的激酶活性介导的。我们现在建议研究表达具有G2019 S突变的全长人LRRK 2或野生型的小鼠模型。我们已经产生了在朊病毒启动子控制下表达LRRK 2的转基因小鼠，其具有中等表型，并且我们最近产生了具有较高表达水平和正常发育的纯合子小鼠。在特定目标1中，我们将表征表达突变体G2019 S LRRK 2的纯合转基因小鼠的存活率和行为，并在适当的细胞群体中对神经元丢失和路易体或其他PD样神经病理学进行初步评估。在特定目标2中，我们将杂合小鼠与使用TH启动子表达α-突触核蛋白截短片段的小鼠杂交。一个新的PD模型，再现在人类疾病中看到的表型方面将是非常有益的。激酶活性的作用的未来研究可以阐明发病机制。此外，LRRK 2激酶可能是一个很好的治疗靶点，小鼠模型将是有价值的临床前治疗试验。 公共卫生相关性：我们建议产生新的帕金森病小鼠模型。LRRK 2突变是人类PD最常见的已确定原因，在某些人群中占PD的20%。我们以前报道过突变体LRRK 2的表达在细胞培养中引起大量的细胞毒性，我们最近发现毒性是通过突变体LRRK 2的激酶活性介导的。一种新的小鼠PD模型，复制在人类疾病中看到的表型方面将是非常有益的。激酶活性的作用的未来研究可以阐明发病机制。此外，LRRK 2激酶可能是一个很好的治疗靶点，小鼠模型将是有价值的临床前治疗试验。

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.