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

• 批准号: 9764564
• 负责人: RICHARD J SMEYNE
• 金额: $ 42.18万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 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/9764564
• 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; Influenza A Virus, H1N1 Subtype; Injections; LRRK2 gene; Lead; Leucine-Rich Repeat; Lewy Bodies; Motor; Motor output; Mus; Mutation; Nervous system structure; Neuraxis; Neurites; 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; influenzavirus; internal control; misfolded protein; monoamine; mutant; neuroinflammation; neuron loss; novel; olfactory bulb; protein aggregate; risk variant; synuclein; synucleinopathy

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 帕金森氏病的病因是多元的，从确定的基因突变到 严格的环境原因。到目前为止，已经确定了18种导致帕金森氏症的基因。 导致帕金森氏症的两个最常见的遗传突变是：1）GBA基因中的突变， 编码葡萄糖脑苷酶蛋白，并在LRRK2基因中进行2）突变，该突变富含亮氨酸重复 激酶II蛋白。除了它们已知的“遗传性遗传性”与疾病原因的关系 GBA和LRRK2基因也被认为是PD发展的“风险因素”，因为 每个患有这些突变的人都会发展出帕金森氏病，只有一秒钟才能表现出来 “打”。无论是PD的发射原因，几乎所有帕金森氏病的病例都有共同的方面 病理学，包括：1）存在聚集的α-核蛋白，2）SNPC DA神经元的丧失和3） 神经炎症的增加。此外，人们还看到认知和电动机输出变化。在这个 应用，我们将检查已知启动帕金森氏病的不同病理机制， 包括蛋白质激酶激活，蛋白质管理或注射将改变/影响聚集 α-Syn在整个神经系统中的传播。具体来说，我们将研究对PD的影响 病理生理学包括SNPC DA神经元丧失，基底神经节儿茶酚胺的丧失，诱导 神经炎症和错误折叠的α-突触核蛋白的传播。我们还将检查认知和运动是否 PFF播种后，在这3个条件下发生行为变化。这些帕金森病将是 在注射α-突触核蛋白（PFF）预先形成的细丝后检查成三个不同的区域 中枢神经系统的中枢神经系统，包括已知参与PD的两个（嗅球和纹状体），一个不是 （内部控制，海马）。在特定目标1中，我们将检查是否注入了不同区域的PFF 在LRRK2基因中携带G2019S突变的小鼠中枢神经系统的中枢神经系统改变了α-Syn的播种和扩散 以及如上所述改变PD中的其他已知病理。在特定目标2中，我们将检查是否 注入载有A的小鼠中枢神经系统区域的α-核蛋白（PFF）的原纤维 L444p GBA突变改变了α-Syn的播种和扩散，并改变了其他已知病理学 如上所述的PD。在特定目标3中，我们将检验以下假设：先前的神经炎性损伤 （感染H1N1影响力病毒）大脑会增加小鼠PFF的播种和扩散 如上所述，携带PD敏感性基因以及更改PD中的其他已知病理。这些 三个目标将使我们能够确定是否有任何一种或多种病理机制（激酶激活 （遗传），蛋白质不当（基因X环境”或病毒感染（环境）直接影响 alpha-甲核蛋白和其他常见的帕金森氏病的传播。