Mechanistic dissection of P-body formation and abnormal mRNA degradation in alpha-synucleinopathy
α-突触核蛋白病中 P 体形成和异常 mRNA 降解的机制解析
基本信息
- 批准号:9808391
- 负责人:
- 金额:$ 49.23万
- 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:2019-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmyloidAntibodiesAttentionAutopsyBiological AssayBiologyBiotinBrainCell Culture TechniquesCell LineCell modelCellsChargeChemistryChronicCo-ImmunoprecipitationsCollaborationsCultured CellsCytoplasmDataDiseaseDisease modelDissectionEpitopesEquilibriumEtiologyEukaryotic CellEventFYN geneFutureG3BP1 geneGenesGeneticGrantHealthcare SystemsHumanInvestigationLabelLeadLewy BodiesLewy Body DementiaLigaseLightLinkMammalian CellMapsMeasuresMediatingMessenger RNAMetabolicMetabolismMethodsModelingMusMutationNatureNerve DegenerationNeurodegenerative DisordersNeuronsOrganellesParkinson DiseaseParkinson&aposs DementiaPathogenesisPathologicPathologyPathway interactionsPatientsPhysiologic pulsePhysiologicalPhysiologyPoint MutationPrevention strategyProteinsProteomeRNA BindingRNA-Binding ProteinsRiskStreptavidinStructureSubstantia nigra structureTechniquesTestingToxic effectUntranslated RNAVesicleYeastsalpha synucleinbasebiological adaptation to stressbrain tissuecase controldeep sequencingdesigndopaminergic neuronexperimental studyflyfrontal lobegenetic analysisin vivoin vivo Modelinduced pluripotent stem cellinterestmRNA DecaymRNA Transcript DegradationmRNA decappingmutantneuropathologynew therapeutic targetnovelnovel therapeuticspreventprotein misfoldingprotein protein interactionresponserisk variantsensorstress granulesynucleinopathytargeted treatmenttemporal measurementtraffickingvesicle-associated membrane protein
项目摘要
PROJECT SUMMARY
There are currently no measures that prevent or slow the course of Parkinson’s disease (PD) and dementia with
Lewy bodies (DLB). These common and devastating “synucleinopathies” are characterized by
neurodegeneration associated with aggregation of the vesicle membrane-associated protein alpha-synuclein (a-
syn). Dominant point mutations, multiplications, and common risk variants at the a-syn gene locus cause or
confer increased risk for PD and DLB, definitively tying this protein to disease etiology. This has raised interest
in therapies that target a-syn toxicity, but this toxicity remains poorly understood. Over the years, our group and
others have developed several distinct cellular models of a-syn toxicity to address the nature of this toxicity,
including PD patient-derived neurons. We have mapped genetic and physical interactions for a-syn. They
predictably drew our attention to vesicle trafficking but, unexpectedly, mRNA metabolism emerged as a novel
pathway tied to a-syn biology. Here, we propose that a-syn is directly linked to Processing-bodies (P-bodies),
cytoplasmic membraneless organelles involved in mRNA degradation and storage. We used a novel protein-
perturbation sensor to narrow down the a-syn specific perturbations in the RNA-binding proteome, and
consequently discovered that increased P-body formation is associated with a-syn mediated toxicity. P-body
formation is conserved in PD patient-derived neurons. This is not a generic stress response. For example, it is
highly distinct from the typical “stress granule” response that occurs in the context of other protein misfolding
events. Furthermore, our preliminary data strongly suggest P-body formation is directly tied to a-syn biology
because we found that a-syn has physical interactions with central components of P-bodies, namely decapping
proteins and associated factors. Now, we have optimized a method using CLICK chemistry-based metabolic
labeling to quantitatively measure mRNA degradation rates. Technologically, we are thus poised to fully
investigate the mechanism by which a-syn aggregation and mislocalization lead to perturbed mRNA metabolism.
We now propose to assay a-syn-P-body interactions and mRNA degradation in a disease-relevant cellular
model, specifically in neurons derived from patients harboring a-synA53T mutation and a-syn-wild type
triplication. We have thoroughly characterized these iPSC lines and generated isogenic mutation-corrected
controls. Finally, we will investigate postmortem brain tissues of PD/DLB patients for elevated levels or
mislocalization of P-bodies to confirm disease-relevance. We provide a roadmap for testing our hypothesis in
the future through genetic analysis in cellular and in vivo models. We believe that the novel link between P-
bodies and a-syn will commence new avenues for understanding the pathologic consequences of a-syn toxicity,
and potentially new therapeutic options for PD and other synucleinopathies.
项目概要
目前尚无任何措施可以预防或减缓帕金森病 (PD) 和痴呆症的病程
路易体 (DLB)。这些常见且具有破坏性的“突触核蛋白病”的特点是
与囊泡膜相关蛋白 α-突触核蛋白 (a-synuclein) 聚集相关的神经变性
同步)。 a-syn 基因位点的显性点突变、倍增和常见风险变异会导致或
增加患 PD 和 DLB 的风险,明确地将这种蛋白质与疾病病因联系起来。这引起了人们的兴趣
在针对 a-syn 毒性的疗法中,但这种毒性仍然知之甚少。多年来,我们集团和
其他人开发了几种不同的 a-syn 毒性细胞模型来解决这种毒性的本质,
包括 PD 患者来源的神经元。我们绘制了 a-syn 的遗传和物理相互作用图。他们
不出所料,我们注意到囊泡运输,但出乎意料的是,mRNA 代谢作为一种新的代谢途径出现了。
与a-syn生物学相关的途径。在这里,我们建议 a-syn 直接链接到处理体(P-bodies),
细胞质无膜细胞器参与 mRNA 降解和储存。我们使用了一种新型蛋白质——
扰动传感器缩小 RNA 结合蛋白质组中 a-syn 特异性扰动的范围,以及
结果发现,P-体形成的增加与a-syn介导的毒性有关。 P体
PD患者来源的神经元的形成是保守的。这不是一般的压力反应。例如,它是
与其他蛋白质错误折叠背景下发生的典型“应激颗粒”反应截然不同
事件。此外,我们的初步数据强烈表明 P-body 的形成与 a-syn 生物学直接相关
因为我们发现a-syn与P体的中心成分有物理相互作用,即脱帽
蛋白质和相关因子。现在,我们优化了一种使用基于 CLICK 化学的代谢方法
标记以定量测量 mRNA 降解率。从技术上讲,我们已做好充分准备
研究 a-syn 聚集和错误定位导致 mRNA 代谢紊乱的机制。
我们现在建议测定疾病相关细胞中的 a-syn-P-body 相互作用和 mRNA 降解
模型,特别是来自携带 a-synA53T 突变和 a-syn 野生型的患者的神经元
三倍。我们已经彻底表征了这些 iPSC 系并生成了同基因突变校正的
控制。最后,我们将调查 PD/DLB 患者死后脑组织的水平是否升高或
P-体的错误定位以确认疾病相关性。我们提供了一个路线图来检验我们的假设
通过细胞和体内模型的遗传分析来预测未来。我们相信 P- 之间的新颖联系
身体和a-syn将为了解a-syn毒性的病理后果开辟新途径,
以及 PD 和其他突触核蛋白病的潜在新治疗选择。
项目成果
期刊论文数量(0)
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 }}
Vikram Khurana其他文献
Vikram Khurana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('Vikram Khurana', 18)}}的其他基金
Investigating physiologic and pathophysiologic connections between the Parkinson's disease protein alpha-synuclein and RNA binding proteins
研究帕金森病蛋白 α-突触核蛋白和 RNA 结合蛋白之间的生理和病理生理联系
- 批准号:
10744556 - 财政年份:2023
- 资助金额:
$ 49.23万 - 项目类别:
Elucidating the biological differences between distinct fibrillar and non-fibrillar alpha-synuclein inclusions in human stem-cell models
阐明人类干细胞模型中不同纤维状和非纤维状 α-突触核蛋白内含物之间的生物学差异
- 批准号:
10401873 - 财政年份:2020
- 资助金额:
$ 49.23万 - 项目类别:
Elucidating the biological differences between distinct fibrillar and non-fibrillar alpha-synuclein inclusions in human stem-cell models
阐明人类干细胞模型中不同纤维状和非纤维状 α-突触核蛋白内含物之间的生物学差异
- 批准号:
10206276 - 财政年份:2020
- 资助金额:
$ 49.23万 - 项目类别:
Elucidating the biological differences between distinct fibrillar and non-fibrillar alpha-synuclein inclusions in human stem-cell models
阐明人类干细胞模型中不同纤维状和非纤维状 α-突触核蛋白内含物之间的生物学差异
- 批准号:
10739667 - 财政年份:2020
- 资助金额:
$ 49.23万 - 项目类别:
Elucidating the Biological Differences Between Distinct Fibrillar and Non-Fibrillar Alpha-Synuclein Inclusions in Human Stem-Cell Models
阐明人类干细胞模型中不同纤维状和非纤维状 α-突触核蛋白内含物之间的生物学差异
- 批准号:
10622480 - 财政年份:2020
- 资助金额:
$ 49.23万 - 项目类别:
Elucidating the biological differences between distinct fibrillar and non-fibrillar alpha-synuclein inclusions in human stem-cell models
阐明人类干细胞模型中不同纤维状和非纤维状 α-突触核蛋白内含物之间的生物学差异
- 批准号:
10052807 - 财政年份:2020
- 资助金额:
$ 49.23万 - 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:
$ 49.23万 - 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:
$ 49.23万 - 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:
$ 49.23万 - 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:
$ 49.23万 - 项目类别:
Fellowship
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:
$ 49.23万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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:
$ 49.23万 - 项目类别:
Research Grant
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:
$ 49.23万 - 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:
$ 49.23万 - 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:
$ 49.23万 - 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:
$ 49.23万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




