Neurodegenerative interactions in conditional LRRK2 Tg models

描述(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，各种基因突变导致帕金森病。在帕金森病的遗传病因中，常染色体显性遗传型家族性帕金森病(FPD)具有许多共同的病理和临床特征，更常见的是晚发型散发性帕金森病。最近，LRRK2基因突变被证明是导致迟发性FPD的变外显性和a-突触核蛋白(a-syn)病理(a-突触核素病)的原因。因此，LRRK2引起的帕金森病可能与环境和遗传因素相互作用。为了了解LRRK2在导致PD伴α-突触核病中的致病作用，我们建立了条件人LRRK2(HLRRK2)转基因(TG)小鼠模型，在该模型中，突变型(R1441C和G2019S)和野生型(WT)hLRRK2在皮质下区域可以获得高水平的表达。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。由于突变的hLRRK2携带者中只有50%的人在70岁内发生帕金森病，突变的hLRRK2可能与其他因素结合起来充分表达致病潜力。我们将通过测试突变的hLRRK2是否增加多巴胺能神经元对多巴胺能毒素的易感性来检验这一假设。进一步，我们将确定突变型hLRRK2和α-Syn之间是否存在病理上的相互作用，从而导致PD相关神经元群体的神经退行性变。

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.