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，各种基因突变在约10%的病例中引起PD。在PD的遗传病因中，常染色体显性遗传的家族性PD（FPD）与更常见的迟发性散发性PD具有许多共同的病理和临床特征。最近，LRRK 2基因的突变被证明会导致迟发性FPD，具有可变的突触率和α-突触核蛋白（α-Syn）病理（α-突触核蛋白病）。因此，由LRRK 2引起的PD可能涉及与环境和遗传因素的相互作用。为了理解LRRK 2在引起具有α-突触核蛋白病的PD中的致病性参与，我们已经产生了条件性人LRRK 2（hLRRK 2）转基因（Tg）小鼠模型，其中可以在皮质下区域中实现高水平的突变体（R1441 C和G2019 S）和野生型（WT）hLRRK 2表达。我们将确定，当表达在皮层下神经元，突变hLRRK 2导致小鼠进行性神经病理学，包括多巴胺能神经元的损失。因为只有~50%的突变hLRRK 2携带者在70岁内发展为PD，突变hLRRK 2可能与其他因素联合收割机结合以充分表达致病潜力。我们将通过测试突变hLRRK 2是否增加多巴胺能神经元对多巴胺能毒素的脆弱性来验证这一假设。此外，我们将确定突变hLRRK 2和a-Syn之间是否存在引起PD相关神经元群体的神经变性的病理相互作用。

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.