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

致病性帕金森病突变在中枢神经系统中α-突触核蛋白播种和传播中的作用

基本信息

批准号：
10382329
负责人：
RICHARD J SMEYNE
金额：
$ 41.31万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382329
关键词：
Affect Basal Ganglia Behavioral Biological Process Brain Brain Stem Ca(2+)-Calmodulin Dependent Protein Kinase Catecholamines Cognitive Communities Corpus striatum structure DNA Sequence Alteration Development Disease Enteral Environment Etiology Filament Functional disorder Gene Activation Genes Genetic Hippocampus (Brain)Human Infection Inflammation Inflammatory Response Influenza A Virus, H1N1 Subtype Injections LRRK2 gene Lead Leucine-Rich Repeat Lewy Bodies Lewy neurites Motor Motor output Mus Mutation Nervous system structure Neuraxis Parkinson Disease Parkinsonian Disorders Pathogenesis Pathogenicity Pathologic Pathologic Processes Pathology Pathway interactions Pattern Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Protein Kinase Proteins Respiratory Tract Infections Risk Risk Factors Role Saline Seeds Susceptibility Gene Symptoms System Testing Virus Diseases alpha synuclein dopaminergic neuron gene environment interaction glucosylceramidase immune activation influenza infection influenzavirus internal control misfolded protein monoamine mutant neuroinflammation neuron loss novel olfactory bulb protein aggregation risk variant synuclein synucleinopathy

项目摘要

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.

抽象的帕金森病的病因是多因素的，从已识别的基因突变到迄今为止，已发现超过 18 个基因会导致帕金森病。导致帕金森病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，2) LRRK2 基因发生突变，富含亮氨酸重复序列激酶 II 蛋白除了与疾病因果关系已知的“遗传即家族”关系外， GBA 和 LRRK2 基因也被认为是 PD 发生的“危险因素”，因为每个携带这些突变的人都会患上帕金森病，并且可能仅在一秒钟后才会显现出来无论帕金森病的病因是什么，几乎所有帕金森病病例都有共同点。病理学，包括：1) 聚集的 α-突触核蛋白的存在，2) SNpc DA 神经元的损失，以及 3) 此外，神经炎症的增加也会导致认知和运动输出的变化。应用程序，我们将检查已知引发帕金森病的不同病理机制，包括蛋白激酶激活、蛋白质管理或炎症都会改变/影响聚集具体来说，我们将检查 α-syn 在整个神经系统中的传播。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、诱导神经炎症和错误折叠的 α-突触核蛋白的扩散我们还将检查认知和运动功能。 PFF 接种后，在这 3 种情况下会发生行为变化，这些帕金森病症状将发生。将预先形成的 α-突触核蛋白 (PFF) 细丝注射到三个不同区域后进行检查中枢神经系统的一部分，包括已知与帕金森病有关的两种（嗅球和纹状体）和一种与帕金森无关的（内部对照，海马体）。在具体目标 1 中，我们将检查 PFF 是否注射到不同区域。 LRRK2 基因中携带 G2019S 突变的小鼠中枢神经系统的变化改变了 α-Syn 的播种和传播以及改变上述 PD 中的其他已知病理，在具体目标 2 中，我们将检查是否。将预先形成的α-突触核蛋白（PFF）原纤维注射到携带a-突触核蛋白的小鼠中枢神经系统的不同区域 L444P 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。在特定目标 3 中，我们将测试先前的神经炎症损伤的假设。（感染 H1N1 流感病毒）到大脑会增加 PFF 在小鼠体内的播种和传播携带帕金森病易感基因并改变上述帕金森病的其他已知病理。三个目标将使我们能够确定这些病理机制中是否有任何一种或多种（激酶激活（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。