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，伴有严重的功能障碍，由黑质和其他大脑区域的神经退行性变引起。LRRK2突变是人类帕金森病最常见的病因，在某些人群中占帕金森病的20%。在欧洲和北美人群中，最常见的突变G2019S存在于高达1%的明显散发性帕金森病中，并导致典型的晚发性帕金森病，对L多巴和路易体病理有反应。我们以前报道过突变型LRRK2的表达在细胞培养中会引起大量的细胞毒性，最近我们发现这种毒性是通过突变型LRRK2的激酶活性来介导的。我们现在建议研究表达带有G2019S突变的全长人类LRRK2或野生型的小鼠模型。我们已经获得了在Prion启动子控制下表达LRRK2的转基因小鼠，具有中等表型，并且我们最近产生了更多表达水平更高、发育正常的纯合子小鼠。在特定目标1中，我们将描述表达突变G2019S LRRK2的纯合子转基因小鼠的存活和行为，并在适当的细胞群体中对神经元丢失和路易小体或其他类似PD的神经病理进行初步评估。在特定目标2中，我们将杂合子小鼠与使用TH启动子表达截短的α-突触核蛋白片段的小鼠进行杂交。一种新的帕金森病模型，能够再现人类疾病中所见的表型特征，将是非常有益的。未来对激酶活性作用的研究可能会阐明发病机制。此外，LRRK2激酶可能是一个很好的治疗靶点，小鼠模型对于临床前治疗试验将是有价值的。 公共卫生相关性：我们建议建立新的帕金森氏病小鼠模型。LRRK2突变是人类帕金森病最常见的病因，在某些人群中占帕金森病的20%。我们以前报道过突变型LRRK2的表达在细胞培养中会引起大量的细胞毒性，最近我们发现这种毒性是通过突变型LRRK2的激酶活性来介导的。一种新的帕金森病小鼠模型将是非常有益的，它可以再现人类疾病中出现的表型的某些方面。未来对激酶活性作用的研究可能会阐明发病机制。此外，LRRK2激酶可能是一个很好的治疗靶点，小鼠模型对于临床前治疗试验将是有价值的。

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.