Defining the Role of Poly ADP-ribose in Biomolecular Condensation in ALS and FTLD
定义聚 ADP-核糖在 ALS 和 FTLD 生物分子缩合中的作用
基本信息
- 批准号:10157522
- 负责人:
- 金额:$ 259.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Alpha GranuleAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisAntineoplastic AgentsAutomobile DrivingBiochemicalBiochemistryBiophysicsBiotinCell modelCellsChemicalsCodeColorComplexCytoplasmic GranulesDetectionExhibitsFDA approvedFluorescenceFluorescence Resonance Energy TransferFluorescent DyesKnowledgeLabelLaboratoriesLeadLengthLinkLiquid substanceMeasuresMediatingMethodsMolecularMolecular AnalysisMolecular BiologyMutationNerve DegenerationNeurodegenerative DisordersNeuronsNucleic AcidsParkinson DiseasePathologicPhasePhysical condensationPoly Adenosine Diphosphate RibosePoly(ADP-ribose) PolymerasesPolymersPositioning AttributePost-Translational Protein ProcessingPreparationPropertyProteinsProteomeProteomicsRNARNA-Binding ProteinsRegulationRibonucleasesRibonucleoproteinsRoleSeedsSolidStructureTestingUniversitiesVariantage relatedage related neurodegenerationbaseempoweredflexibilityfluidityfrontotemporal lobar dementia-amyotrophic lateral sclerosisinhibitor/antagonistmolecular imagingmutantneuropathologyneurotoxicneurotoxicitynovelprotein aggregationrecruitsarcomasingle moleculesingle-molecule FRETstress granuletherapy developmentviscoelasticity
项目摘要
PROJECT SUMMARY
Poly ADP-ribose (PAR) is an RNA-like protein modification whose dysregulation is linked to age-
dependent neurodegenerative diseases including ALS, Parkinson’s and Alzheimer’s disease.
PAR is a core component of stress granules, a type of membraneless ribonucleoprotein (RNP)
granules that can seed aberrant protein aggregation leading to neuropathology. Unlike RNA, PAR
can form into both linear and branched structures. Strikingly, inhibitors of PAR polymerase, which
is a class of FDA-approved anticancer drugs, were shown to mitigate neurotoxicity in cell models
of neurodegeneration, reflecting a potential role of PAR in neurotoxicity. Two laboratories at Johns
Hopkins University led by Sua Myong (Biophysics department) and Anthony K. L. Leung
(Department of Biochemistry and Molecular Biology ) bring together orthogonal expertise in
molecular imaging, chemical and proteomic methods to investigate the molecular basis of PAR-
driven protein condensation and aggregation mechanism responsible for neurodegenerative
diseases, which may pave new ways of developing therapy. Our recent discovery of a PAR
modifying method (Leung et al, Mol Cell, 2019) and mechanism of FUS liquid-liquid phase
separation in ALS/FTLD-linked cases (Myong et al, Mol Cell, 2019) places us in an ideal position
for tackling the poorly understood role of PAR in biomolecular condensation implicated in
neurodegenerative diseases. In Preliminary Studies, we discovered that (i) PAR is extremely
potent in condensing FUS (fused in sarcoma), an RNA binding protein localized in stress granules
and implicated in ALS/FTLD and (ii) PAR targeted proteome is enriched in stress granule
components. Building on these exciting results, we propose to uncover the role of PAR in driving
biomolecular condensation by employing single molecule, biochemical, meso-scale, biophysical
and cellular platforms.
项目摘要
聚ADP-核糖(PAR)是一种RNA样蛋白质修饰,其失调与年龄有关。
依赖性神经退行性疾病,包括ALS、帕金森病和阿尔茨海默病。
PAR是一种无膜核糖核蛋白(RNP),是应激颗粒的核心成分
这些颗粒可导致异常蛋白质聚集,从而导致神经病理学。与RNA不同,PAR
可以形成直链和支链结构。引人注目的是,PAR聚合酶的抑制剂,
是一类FDA批准的抗癌药物,在细胞模型中显示可减轻神经毒性
的神经变性,反映了潜在的作用PAR的神经毒性。约翰的两个实验室
霍普金斯大学的Sua Myong(生物物理系)和Anthony K. L.梁
(生物化学和分子生物学系)汇集了正交专业知识,
分子成像、化学和蛋白质组学方法来研究PAR的分子基础,
导致神经退行性变的蛋白质凝聚和聚集机制
疾病,这可能为开发治疗方法铺平新的道路。我们最近发现了一种PAR
FUS液-液相的修饰方法(Leung et al,Mol Cell,2019)和机理
ALS/FTLD相关病例的分离(Myong et al,Mol Cell,2019)使我们处于理想的位置
用于解决PAR在生物分子缩合中的作用,
神经退行性疾病在初步研究中,我们发现(i)PAR是非常
在浓缩FUS(融合于肉瘤中)中有效,FUS是一种定位于应激颗粒中的RNA结合蛋白
并牵连ALS/FTLD和(ii)PAR靶向蛋白质组是丰富的应激颗粒
件.基于这些令人兴奋的结果,我们建议揭示PAR在驾驶中的作用。
通过使用单分子、生物化学、介观尺度、生物物理
和蜂窝平台。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Single-molecule and ensemble methods to probe RNP nucleation and condensate properties.
- DOI:10.1016/j.ymeth.2021.02.012
- 发表时间:2022-01
- 期刊:
- 影响因子:0
- 作者:Rhine K;Skanchy S;Myong S
- 通讯作者:Myong S
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Anthony K L Leung其他文献
Anthony K L Leung的其他文献
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{{ truncateString('Anthony K L Leung', 18)}}的其他基金
Role of ADP-ribosylation in Stress Granules
ADP-核糖基化在应激颗粒中的作用
- 批准号:
10388732 - 财政年份:2015
- 资助金额:
$ 259.31万 - 项目类别:
Post-transcriptional Gene Regulation by Cytoplasmic Poly(ADP-ribose) Polymerases
细胞质聚(ADP-核糖)聚合酶的转录后基因调控
- 批准号:
9234547 - 财政年份:2015
- 资助金额:
$ 259.31万 - 项目类别:
Role of ADP-ribosylation in Stress Granules
ADP-核糖基化在应激颗粒中的作用
- 批准号:
10703465 - 财政年份:2015
- 资助金额:
$ 259.31万 - 项目类别:
Post-transcriptional Gene Regulation by Cytoplasmic Poly(ADP-ribose) Polymerases
细胞质聚(ADP-核糖)聚合酶的转录后基因调控
- 批准号:
8886016 - 财政年份:2015
- 资助金额:
$ 259.31万 - 项目类别:
Role of ADP-Ribosylation in Stress Granules-Equipment Supplement
ADP-核糖基化在应激颗粒-设备补充剂中的作用
- 批准号:
10683638 - 财政年份:2015
- 资助金额:
$ 259.31万 - 项目类别:
Role of ADP-ribosylation in Stress Granules
ADP-核糖基化在应激颗粒中的作用
- 批准号:
10268197 - 财政年份:2015
- 资助金额:
$ 259.31万 - 项目类别:
Role of ADP-ribosylation in Stress Granules
ADP-核糖基化在应激颗粒中的作用
- 批准号:
9973639 - 财政年份:2015
- 资助金额:
$ 259.31万 - 项目类别: