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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：
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
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/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

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.

摘要