Role of pathogenic Parkinsonian mutations in the seeding and propagation of alpha-synuclein in the CNS

摘要 帕金森病的病因是多方面的，从已确定的基因突变到 严格的环境因果关系到目前为止，已经确定了超过18个导致帕金森症的基因。 导致帕金森症的两种最常见的基因突变是：1）GBA基因突变， 编码葡萄糖脑苷脂酶蛋白，和2）LRRK 2基因中的突变， 激酶II蛋白。除了他们已知的“遗传即家族”的关系，疾病的原因， GBA和LRRK 2基因也被认为是PD发展“危险因素”，因为没有 每个有这些突变的人都会患上帕金森病， “击中”。无论帕金森病的起始原因是什么，几乎所有的帕金森病病例都有共同的方面 包括：1）聚集的α-突触核蛋白的存在，2）SNpc DA神经元的损失和3） 神经炎症的增加此外，还可以看到认知和运动输出的变化。在这 应用，我们将研究不同的病理机制已知启动帕金森病， 包括蛋白激酶激活、蛋白管理或炎症将改变/影响聚集 并在整个神经系统中扩散具体来说，我们将研究对PD的影响 病理生理学包括SNpc DA神经元损失、基底神经节儿茶酚胺损失、 神经炎症和错误折叠的α-突触核蛋白的扩散。我们还将研究认知和运动 PFF接种后，在这3种条件下发生行为变化。这些帕金森病将是 将预先形成的α-突触核蛋白（PFF）丝注入三个不同的区域后进行检查 包括两个已知参与PD（嗅球和纹状体）和一个不参与PD（嗅球和纹状体） （内部对照，海马）。在具体目标1中，我们将检查是否将PFF注入不同区域 在LRRK 2基因中携带G2019 S突变的小鼠的CNS中， 以及如上所述改变PD中的其它已知病理。在具体目标2中，我们将研究 将预先形成的α-突触核蛋白（PFF）纤维注射到携带α-突触核蛋白的小鼠的CNS的不同区域中， L444 P GBA突变改变了α-Syn的播种和传播，并改变了其他已知的病理学。 如上所述的PD。在具体目标3中，我们将检验先前的神经炎性损伤 （感染H1N1流感病毒）进入大脑将增加PFF在小鼠体内的播种和传播 携带PD易感基因以及改变如上所述的PD中的其它已知病理。这些 三个目标将允许我们确定这些病理机制中的任何一个或多个（激酶激活）是否 （遗传），蛋白质处理不当（基因x环境）或病毒感染（环境）直接影响 错误折叠的α-突触核蛋白和其他常见帕金森病的传播。

Abstract The etiology of Parkinson’s disease is multivariate, ranging from identified genetic mutations to strict environmental causation. So far, more than 18 genes have been identified that result in parkinsonism. The two most common genetic mutations that lead to parkinsonism are: 1) mutations in the GBA gene that encodes the glucocerebrosidase protein, and 2) mutations in the LRRK2 gene that Leucine Rich Repeat Kinase II protein. In addition to their known “genetic i.e familial” relationship to disease causation, both the GBA and LRRK2 genes are also considered to be “risk factors” for development of PD, in that not everyone with these mutations develops Parkinson’s disease and they may only manifest after a second “hit”. No matter the initiating cause of PD, almost all cases of Parkinson’s disease share common aspects of pathology, including: 1) the presence of aggregated alpha-synuclein, 2) loss of SNpc DA neurons and 3) an increase in neuroinflammation. Additionally, one also sees cognitive and motor output changes. In this application, the we will examine different pathological mechanisms known to initiate Parkinson’s disease, including protein kinase activation, protein management or inflammation will alter/affect the aggregation and spread of α-syn throughout the nervous system. Specifically, we will examine the effect on PD pathophysiology including SNpc DA neuron loss, loss of basal ganglia catecholamines, induction of neuroinflammation and spread of misfolded alpha-synuclein. We will also examine if cognitive and motor behavioral changes occur in these 3 conditions after PFF seeding. These parkinsonian pathologies will be examined following injection of preformed filaments of alpha-synuclein (PFFs) into three different regions of the CNS, including two known to be involved in PD (olfactory bulb and striatum) and one that is not (internal control, hippocampus). In Specific Aim 1, we will examine if PFFs injected into different regions of the CNS of mice carrying a G2019S mutation in the LRRK2 gene alter the seeding and spread of α-Syn as well as alter other known pathologies in PD as described above. In Specific Aim 2, we will examine if preformed fibrils of alpha-synuclein (PFFs) injected into different regions of the CNS of mice carrying a L444P GBA mutation alters the seeding and spread of α-Syn as well as alter other known pathologies in PD as described above. In Specific Aim 3 we will test the hypothesis that a prior neuroinflammatory insult (infection with the H1N1 influenza virus) to the brain will increase the seeding and spread of PFFs in mice carrying PD susceptibility genes as well as alter other known pathologies in PD as described above. These three aims will allow us to determine if any one or more of these pathological mechanisms (kinase activation (genetic), protein mishandling (gene x environment” or viral infection (environment) directly influence the spread of misfolded alpha-synuclein and other common parkinsonian pathologies.