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:10599135
- 负责人:
- 金额:$ 41.31万
- 依托单位:
- 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:
- 关键词:AffectBasal GangliaBehavioralBiological ProcessBrainBrain StemCa(2+)-Calmodulin Dependent Protein KinaseCatecholaminesCentral Nervous SystemCognitiveCommunitiesCorpus striatum structureDNA Sequence AlterationDevelopmentDiseaseEnteralEnvironmentEtiologyFilamentFunctional disorderGene ActivationGenesGeneticHippocampusHumanInfectionInflammationInflammatory ResponseInfluenza A Virus, H1N1 SubtypeInjectionsLRRK2 geneLeucine-Rich RepeatLewy BodiesLewy neuritesMotorMotor outputMusMutationNervous SystemParkinson DiseaseParkinsonian DisordersPathogenesisPathogenicityPathologicPathologic ProcessesPathologyPathway interactionsPatternPhosphorylationPhosphotransferasesPost-Translational Protein ProcessingPredispositionProtein KinaseProteinsRespiratory Tract InfectionsRiskRisk FactorsRoleSalineSusceptibility GeneSymptomsSystemTestingVirus Diseasesalpha synucleindopaminergic neurongene environment interactionglucosylceramidaseimmune activationinfluenza infectioninfluenzavirusinternal controlmisfolded proteinmonoaminemutantneuroinflammationneuron lossnovelolfactory bulbpre-formed fibrilprotein aggregationrisk variantsynergismsynucleinsynucleinopathy
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
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”。无论帕金森病的最初原因是什么,几乎所有帕金森病病例都有共同点
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。
项目成果
期刊论文数量(0)
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RICHARD J SMEYNE其他文献
RICHARD J SMEYNE的其他文献
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{{ truncateString('RICHARD J SMEYNE', 18)}}的其他基金
Synergistic Interactions of SARs-CoV2 and environmental toxicants in Experimental Parkinsonism
SARs-CoV2 与环境毒物在实验性帕金森病中的协同相互作用
- 批准号:
10316307 - 财政年份:2021
- 资助金额:
$ 41.31万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 41.31万 - 项目类别:
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:
10382329 - 财政年份:2019
- 资助金额:
$ 41.31万 - 项目类别:
H5N1 Influenza Virus as a Novel Etiological Agent in Parkinsons Disease
H5N1 流感病毒作为帕金森病的新病原体
- 批准号:
7825434 - 财政年份:2009
- 资助金额:
$ 41.31万 - 项目类别:
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