Neurodegenerative interactions in conditional LRRK2 Tg models

描述（由申请人提供）：帕金森病（PD）是一种常见的神经退行性疾病，约90%的病例病因不明。然而，在约10%的病例中，多种基因突变导致PD。在PD的遗传原因中，常染色体显性家族性PD （FPD）具有许多病理和临床特征，更常见的是晚发散发性PD。最近，LRRK2基因突变被证明可导致具有可变外显率和a-synuclein （a-Syn）病理（a-synucleinopathy）的迟发性FPD。因此，LRRK2引起的PD可能与环境和遗传因素相互作用。为了了解LRRK2在PD伴a-突触核蛋白病中的致病作用，我们建立了条件人LRRK2 （hLRRK2）转基因（Tg）小鼠模型，在皮质下区域可以实现高水平突变体（R1441C和G2019S）和野生型（WT） hLRRK2的表达。我们将确定，当在皮质下神经元中表达时，突变的hLRRK2会导致小鼠进行性神经病理，包括多巴胺能神经元的丧失。由于只有约50%的突变型hLRRK2携带者在70岁以内发生PD，突变型hLRRK2可能与其他因素联合，充分表达致病潜能。我们将通过测试突变体hLRRK2是否增加多巴胺能神经元对多巴胺能毒素的易感性来验证这一假设。进一步，我们将确定突变体hLRRK2和a- syn之间是否存在病理相互作用，导致PD相关神经元群的神经变性。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common neurodegenerative disease where the causes of the disease are unknown for ~90% of cases. However, a variety of genetic mutations cause PD in ~10% cases. Among the genetic causes of PD, autosomal dominant forms of familial PD (FPD) share many of the pathological and clinical features with more common late onset sporadic PD. Recently, mutations in LRRK2 gene were shown to cause late-onset FPD with variable penetrance and a-synuclein (a-Syn) pathology (a-synucleinopathy). Thus, PD caused by LRRK2 may involve interactions with environmental and genetic factors. To understand the pathogenic involvement of LRRK2 in causing PD with a-synucleinopathy, we have generated conditional human LRRK2 (hLRRK2) transgenic (Tg) mouse model where high-levels of mutant (R1441C and G2019S) and wild type (WT) hLRRK2 expression can be achieved in subcortical regions. We will determine that when expressed in subcortical neurons, mutant hLRRK2 causes progressive neuropathology in mice, including the loss of dopaminergic neurons. Because only ~50% of mutant hLRRK2 carriers develop PD within 70 years of age, mutant hLRRK2 may combine with other factors to fully express the pathogenic potential. We will test this hypothesis by testing whether mutant hLRRK2 increases vulnerability in dopaminergic neurons to dopaminergic toxin. Further, we will determine whether there is a pathologic interaction between mutant hLRRK2 and a-Syn in causing neurodegeneration of PD relevant neuronal populations. PUBLIC HEALTH RELEVANCE: Mutations in LRRK2 are the most common genetic cause of late onset PD and resemble sporadic PD. By producing and studying transgenic mouse model with LRRK2-dependent neurodegeneration, we hope to gain new insights about the pathogenesis of PD. Such information will lead to novel therapeutic targets for PD.