Role of Transglutaminase 2 in Synucleinopathies
转谷氨酰胺酶 2 在突触核蛋白病中的作用
基本信息
- 批准号:10285001
- 负责人:
- 金额:$ 43.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmyloid FibrilsAnatomyAnimal ModelAnimalsAttenuatedBehavioralBiological ModelsBrainBrain DiseasesBrain regionCellsCerebrospinal FluidDataDementia with Lewy BodiesDiseaseDisease ProgressionEndopeptidase KExhibitsGenesGeneticGlutamineGoalsGuanosine Triphosphate PhosphohydrolasesHumanIn VitroInjectionsInvestigationKnock-outKnowledgeLewy BodiesLewy neuritesLysineMammalian CellMediatingModelingMolecularMolecular ConformationMolecular WeightMotorMusNatureNerve DegenerationNeuronsOutcomeParkinson DiseaseParkinson&aposs DementiaPathogenicityPathologicPathologic ProcessesPathologyPatientsPerformancePhenotypePlayProcessProtein Disulfide IsomeraseProtein-Serine-Threonine KinasesProteinsProteolysisResistanceRoleSeedsSeveritiesStressStudy modelsSubstantia nigra structureTestingTherapeuticThioflavin STransgenic MiceTransgenic OrganismsTransglutaminasesWild Type MouseYeastsalpha synucleinbasebehavioral phenotypingcrosslinkdesigndopaminergic neuroninhibitor/antagonistmRNA Expressionmonomermutantneuroinflammationphenotypic biomarkerpreservationprotein aggregationprotein expressionresponsesynucleinopathytransglutaminase 2
项目摘要
Project Summary:
α-Synuclein is a key pathogenic protein in Parkinson’s disease (PD) and Dementia with Lewy
Bodies (DLB) based on genetic, neuropathologic, cell biologic and animal model studies. This
intrinsically disordered protein can oligomerize, misfold, and form fibrils that propagate across
neurons in the brain and accumulate in Lewy bodies and Lewy neurites. It is believed that the
oligomeric forms of α-synuclein represent the toxic species, and these can nucleate monomers
to perpetuate the pathologic process underlying the progressive nature of the disease. Thus,
understanding the factors that trigger the initial steps of oligomerization is critical for designing
disease modifying therapeutic strategies. A hitherto under-explored factor is molecular cross-
linking of α-synuclein by transglutaminase 2 (TG2) between glutamine and lysine residues
creating intermolecular isopeptide bonds that are highly resistant to proteolysis. Several lines of
evidence indicate that TG2 cross-links α-synuclein leading to its aggregation in vitro, in cultured
mammalian cells, in yeast cells, and in the brains of transgenic mice. We have found that the
phenotype of α-synuclein transgenic mice is exacerbated by over-expressing TG2 and is
mitigated by knocking it out. Studies in patients with α-synucleinopathy also corroborate the
hypothesis that TG2 plays a pathogenetic role. TG2 expression is increased in the substantia
nigra and cerebrospinal fluid of PD patients compared with control subjects, TG2 co-localizes with
α-synuclein aggregates in stressed dopaminergic neurons in PD brains, and TG2-catalyzed
cross-links co-localize with α-synuclein in Lewy bodies in PD and DLB affected brains. Despite
this body of evidence, it remains unknown whether TG2-mediated cross-linking of α-synuclein
promotes the propagation of these aggregates across the brain. We hypothesize that it does and
propose to test this hypothesis through two specific aims: 1) Investigate if the presence of TG2
and its expression level influence the propagation of α-synuclein fibrils, and 2) Examine if the
transglutaminase enzymatic activity of TG2 is responsible for this process. Knowledge gained
from these studies will address a fundamental scientific question about the pathogenetic
mechanism of TG2-mediated α-synuclein propagation and aid in developing targeted disease
modifying therapeutic for synucleinopathies.
项目总结:
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
M. Maral Mouradian其他文献
M. Maral Mouradian的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('M. Maral Mouradian', 18)}}的其他基金
PME-1: Pathogenetic Role and Therapeutic Opportunity in Neurodegenerative Mixed Proteinopathies
PME-1:神经退行性混合蛋白病的致病作用和治疗机会
- 批准号:
10595891 - 财政年份:2023
- 资助金额:
$ 43.18万 - 项目类别:
Alzheimer’s Disease Protection by Reduced Adenylyl Cyclase Type 5
通过减少 5 型腺苷酸环化酶来预防阿尔茨海默病
- 批准号:
10526756 - 财政年份:2022
- 资助金额:
$ 43.18万 - 项目类别:
Training in Translating Neuroscience to Therapies
将神经科学转化为治疗的培训
- 批准号:
10442401 - 财政年份:2021
- 资助金额:
$ 43.18万 - 项目类别:
Training in Translating Neuroscience to Therapies
将神经科学转化为治疗的培训
- 批准号:
10204266 - 财政年份:2021
- 资助金额:
$ 43.18万 - 项目类别:
Training in Translating Neuroscience to Therapies
将神经科学转化为治疗的培训
- 批准号:
10621360 - 财政年份:2021
- 资助金额:
$ 43.18万 - 项目类别:
PP2A Dysregulation in the Pathogenesis of alpha-Synucleinopathies
α-突触核蛋白病发病机制中的 PP2A 失调
- 批准号:
9920223 - 财政年份:2017
- 资助金额:
$ 43.18万 - 项目类别:
Manipulating Gene Expression in the Dyskinesias of Parkinson's Disease
操纵帕金森病运动障碍中的基因表达
- 批准号:
9305587 - 财政年份:2016
- 资助金额:
$ 43.18万 - 项目类别:
Synergistic Neuroprotective Mechanisms of Coffee Components in Parkinson's Diseas
咖啡成分对帕金森病的协同神经保护机制
- 批准号:
8700581 - 财政年份:2012
- 资助金额:
$ 43.18万 - 项目类别:
Synergistic Neuroprotective Mechanisms of Coffee Components in Parkinson's Diseas
咖啡成分对帕金森病的协同神经保护机制
- 批准号:
8368832 - 财政年份:2012
- 资助金额:
$ 43.18万 - 项目类别:
Synergistic Neuroprotective Mechanisms of Coffee Components in Parkinson's Diseas
咖啡成分对帕金森病的协同神经保护机制
- 批准号:
8543640 - 财政年份:2012
- 资助金额:
$ 43.18万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 43.18万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 43.18万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 43.18万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 43.18万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 43.18万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 43.18万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 43.18万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 43.18万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 43.18万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 43.18万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




