Defining the Role of Poly ADP-ribose in Biomolecular Condensation in ALS and FTLD
Defining the Role of Poly ADP-ribose in Biomolecular Condensation in ALS and FTLD
批准号:
10157522
负责人:
Anthony K L Leung
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
项目状态:
已结题
起止时间:
2020-09-30 至 2024-08-31
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
中文摘要
项目总结
聚腺苷二磷酸核糖(PAR)是一种类似RNA的蛋白质修饰,其失调与年龄有关。
依赖性神经退行性疾病包括肌萎缩侧索硬化症、帕金森氏症和阿尔茨海默病。
PAR是应激颗粒的核心成分,是一种无膜核糖核蛋白(Rnp)。
可导致异常蛋白质聚集导致神经病理的颗粒。与RNA不同,PAR
可以形成线形和分枝结构。引人注目的是,PAR聚合酶的抑制剂,
是FDA批准的一类抗癌药物,在细胞模型中被证明可以减轻神经毒性
神经退行性变,反映PAR在神经毒性中的潜在作用。约翰斯的两个实验室
由Sua Myong(生物物理系)和Anthony K.L.Leung领导的霍普金斯大学
(生物化学和分子生物学系)汇集了
分子成像、化学和蛋白质组学方法研究PAR-1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。我们最近发现的一种标准杆
FUS液-液相的改性方法(Leung等,Mol Cell,2019)及其机理
ALS/FTLD相关病例的分离(Myong等人,Mol Cell,2019)将我们置于理想位置
解决了PAR在生物分子缩合中所起的鲜为人知的作用
神经退行性疾病。在初步研究中,我们发现(I)PAR是非常
一种位于应激颗粒中的RNA结合蛋白,能有效凝聚FUS(在肉瘤中融合)
与ALS/FTLD有关;(Ii)PAR靶向蛋白质组富含应激颗粒
组件。在这些令人兴奋的结果的基础上,我们建议揭示标准杆在驾驶中的作用
利用单分子、生化、中尺度、生物物理进行生物分子缩合
和蜂窝平台。
英文摘要
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.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1016/j.ymeth.2021.02.012
发表时间:
2022-01
期刊:
Methods (San Diego, Calif.)
影响因子:
--
作者:
[Rhine K, Skanchy S, Myong S]
通讯作者:
Myong S
Role of ADP-ribosylation in Stress Granules
-
批准号:10388732
-
项目类别:
-
资助金额:$25.0万
-
财政年份:2015
-
负责人:Anthony K L Leung
-
依托单位:
Post-transcriptional Gene Regulation by Cytoplasmic Poly(ADP-ribose) Polymerases
-
批准号:9234547
-
项目类别:
-
资助金额:$34.74万
-
财政年份:2015
-
负责人:Anthony K L Leung
-
依托单位:
Role of ADP-ribosylation in Stress Granules
-
批准号:10703465
-
项目类别:
-
资助金额:$40.17万
-
财政年份:2015
-
负责人:Anthony K L Leung
-
依托单位:
Post-transcriptional Gene Regulation by Cytoplasmic Poly(ADP-ribose) Polymerases
-
批准号:8886016
-
项目类别:
-
资助金额:$34.72万
-
财政年份:2015
-
负责人:Anthony K L Leung
-
依托单位:
Role of ADP-Ribosylation in Stress Granules-Equipment Supplement
-
批准号:10683638
-
项目类别:
-
资助金额:$2.81万
-
财政年份:2015
-
负责人:Anthony K L Leung
-
依托单位:
Role of ADP-ribosylation in Stress Granules
-
批准号:10268197
-
项目类别:
-
资助金额:$40.21万
-
财政年份:2015
-
负责人:Anthony K L Leung
-
依托单位:
Role of ADP-ribosylation in Stress Granules
-
批准号:9973639
-
项目类别:
-
资助金额:$40.22万
-
财政年份:2015
-
负责人:Anthony K L Leung
-
依托单位: