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:
- 金额:$ 42.18万
- 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 KinaseCatecholaminesCognitiveCommunitiesCorpus striatum structureDNA Sequence AlterationDevelopmentDiseaseEnteralEnvironmentEtiologyFilamentFunctional disorderGene ActivationGenesGeneticHippocampus (Brain)HumanInfectionInflammationInflammatory ResponseInfluenzaInfluenza A Virus, H1N1 SubtypeInjectionsLRRK2 geneLeadLeucine-Rich RepeatLewy BodiesMotorMotor outputMusMutationNervous system structureNeuraxisNeuritesParkinson DiseaseParkinsonian DisordersPathogenesisPathogenicityPathologicPathologic ProcessesPathologyPathway interactionsPatternPhosphorylationPhosphotransferasesPlayPost-Translational Protein ProcessingProtein KinaseProteinsRespiratory Tract InfectionsRiskRisk FactorsRoleSalineSeedsSusceptibility GeneSymptomsSystemTestingVirus Diseasesalpha synucleindopaminergic neurongene environment interactionglucosylceramidaseimmune activationinfluenzavirusinternal controlmisfolded proteinmonoaminemutantneuroinflammationneuron lossnovelolfactory bulbprotein aggregaterisk variantsynucleinsynucleinopathy
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
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:
$ 42.18万 - 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:
10599135 - 财政年份:2019
- 资助金额:
$ 42.18万 - 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:
$ 42.18万 - 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:
$ 42.18万 - 项目类别:
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