Combinatorial effects of PTMs on a-Synuclein structure, function and aggregation
PTM 对 a-Synuclein 结构、功能和聚集的组合效应
基本信息
- 批准号:10391709
- 负责人:
- 金额:$ 170.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAddressAlzheimer&aposs DiseaseAutopsyBehaviorBindingBiochemicalBiological AssayBiologyBiophysicsCellular biologyChemicalsCollaborationsComplexDataDementiaDementia with Lewy BodiesDepositionDiseaseEnvironmental Risk FactorExhibitsFiberFluorescenceGenesHeterogeneityIn VitroIndividualInheritedIsotope LabelingJointsKineticsLabelLeadLewy Body DementiaLigationLinkLipid BilayersLiteratureMass Spectrum AnalysisModificationMolecularMolecular ConformationMultiple System AtrophyMutagenesisMutationN-terminalNeurodegenerative DisordersNeuronsParkinson DiseasePathologicPathologyPatientsPersonsPhosphorylationPhysiologicalPlayPoint MutationPolymorphPost-Translational Protein ProcessingPropertyProteinsPublicationsReactionRecording of previous eventsReportingResearchRoleSamplingSeedsSingle Nucleotide PolymorphismSiteStructureSulfhydryl CompoundsTestingTherapeuticTissuesUbiquitinationVariantWorkalpha synucleinbasebiophysical analysisbiophysical propertieschemical groupcombinatorialdesignexperimental studyglycationinsightmembermonomernovelnovel therapeutic interventionpeptide chemical synthesisprion-likesingle moleculestructural biologysuccesssynucleinopathytargeted treatmenttherapy developmentunnatural amino acidsuptake
项目摘要
α-Synuclein is a small neuronal protein that is the primary component of the proteinaceous aggregates that are the hallmark of Parkinson’s disease (PD), Lewy body dementia (LBD), multiple system atrophy (MSA) and other synucleinopathies, as well as being implicated in related neurodegenerative diseases such as Alzheimer’s disease. Despite intense study, an understanding of the environmental factors which lead to αS aggregation in PD and to differences in aggregation in LBD and MSA is still lacking. Recent evidence supports the idea that structural differences between α-Synuclein aggregates, or ‘strains’, underlie different synucleinopathies. While the molecular details are not yet well understood, it has been suggested that post-translational modifications to α-Synuclein may underlie conformational differences between ‘strains’. However, understanding how these modifications impact aggregate structure, and ultimately pathology, is extremely challenging, both given the large number of reported post-translational modifications to α-Synuclein, as well as their heterogeneous distribution in patient derived samples. From a biochemical and biophysical perspective, many of these modifications have been addressed individually and found to have striking impacts on α-Synuclein properties, including aggregation kinetics and cellular uptake and seeding. However, there is a significant gap in our understanding of how multiple simultaneous modifications may work cooperatively to alter aggregate structure or α-Synuclein function. Our proposed research will address this deficit by taking advantage of the collective expertise of the three PIs in protein chemical synthesis, cellular and molecular biophysics, and structural biology. This will include using a novel semi-synthesis strategy – combining unnatural amino acid mutagenesis, chemoenzymatic modification, thiol-ene reactions, and native chemical ligation – to produce α-Synuclein site specifically modified both at single and multiple sites (Aim 1); determining the impact of α-Synuclein modifications on functional interactions with lipid bilayers, on the kinetics of self-association and on the structural features of the aggregates (Aim 2); and relating these structural effects to internalization of α-Synuclein by primary neurons, and subsequent seeded aggregation of endogenous α-Synuclein (Aim 3). We have selected seven different disease-associated sites on α-Synuclein that are subject to modification with diverse groups, including phosphorylation, acetylation and ubiquitination, and we will compare and contrast the individual effects of these modifications as well as their cross-talk. Our focus is on modifications that are differentially found in PD, LBD, and MSA patient tissues and for which available structural data allow us to propose clear mechanistic hypotheses. We expect to characterize the impact of these modifications both on α-Synuclein functional interactions as well as fibrillar structure and spread. The resulting impact will be in providing a thorough understanding of the molecular basis of ‘strain’ differences in synucleinopathies and guiding the development of therapies targeted at post-translational modifications, or even entirely new therapeutic strategies for synucleinopathies and related dementias.
α-突触核蛋白是一种小的神经元蛋白,其是蛋白质聚集体的主要组分,所述蛋白质聚集体是帕金森病(PD)、路易体痴呆(LBD)、多系统萎缩(MSA)和其他突触核蛋白病的标志,以及涉及相关的神经退行性疾病如阿尔茨海默病。尽管进行了大量的研究,但对导致PD中αS聚集以及LBD和MSA中聚集差异的环境因素仍然缺乏了解。最近的证据支持α-突触核蛋白聚集体或“应变”之间的结构差异是不同突触核蛋白病的基础的观点。虽然分子细节还没有很好地理解,但已经表明α-突触核蛋白的翻译后修饰可能是“菌株”之间构象差异的基础。然而,了解这些修饰如何影响聚集体结构并最终影响病理学是极其具有挑战性的,这是因为报告了大量α-突触核蛋白的翻译后修饰,以及它们在患者来源的样品中的异质性分布。从生物化学和生物物理学的角度来看,这些修饰中的许多已经被单独解决,并发现对α-突触核蛋白性质具有显著影响,包括聚集动力学和细胞摄取和接种。然而,在我们理解多个同时修饰如何协同工作以改变聚集体结构或α-突触核蛋白功能方面存在重大差距。我们提出的研究将通过利用蛋白质化学合成,细胞和分子生物物理学以及结构生物学三个PI的集体专业知识来解决这一缺陷。这将包括使用一种新的半合成策略-结合非天然氨基酸诱变、化学酶修饰、硫醇-烯反应和天然化学连接-以产生在单个和多个位点处特异性修饰的α-突触核蛋白位点(Aim 1);确定α-突触核蛋白修饰对与脂质双层的功能性相互作用的影响,自缔合动力学和聚集体的结构特征(目的2);并将这些结构效应与原代神经元对α-突触核蛋白的内化以及随后内源性α-突触核蛋白的种子聚集(目的3)相关联。我们选择了α-突触核蛋白上七个不同的疾病相关位点,这些位点受到不同基团的修饰,包括磷酸化,乙酰化和泛素化,我们将比较和对比这些修饰的个体效应以及它们的串扰。我们的重点是在PD,LBD和MSA患者组织中发现的差异性修饰,并且可用的结构数据使我们能够提出明确的机制假设。我们期望表征这些修饰对α-突触核蛋白功能相互作用以及纤维状结构和扩散的影响。由此产生的影响将是在提供一个彻底的了解突触核蛋白病的“应变”差异的分子基础,并指导开发针对翻译后修饰的疗法,甚至是突触核蛋白病和相关痴呆症的全新治疗策略。
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)
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Ernest James Petersson其他文献
Ernest James Petersson的其他文献
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{{ truncateString('Ernest James Petersson', 18)}}的其他基金
Bruker RapifleX MALDI TOF/TOF Mass Spectrometer
Bruker RapifleX MALDI TOF/TOF 质谱仪
- 批准号:
10177330 - 财政年份:2021
- 资助金额:
$ 170.61万 - 项目类别:
Studying Aggregation in Neurodegenerative Disease Using Synthetic Proteins
使用合成蛋白质研究神经退行性疾病中的聚集
- 批准号:
10339425 - 财政年份:2019
- 资助金额:
$ 170.61万 - 项目类别:
Studying Aggregation in Neurodegenerative Disease Using Synthetic Proteins
使用合成蛋白质研究神经退行性疾病中的聚集
- 批准号:
10021260 - 财政年份:2019
- 资助金额:
$ 170.61万 - 项目类别:
Studying Aggregation in Neurodegenerative Disease Using Synthetic Proteins
使用合成蛋白质研究神经退行性疾病中的聚集
- 批准号:
10133161 - 财政年份:2019
- 资助金额:
$ 170.61万 - 项目类别:
Studying Aggregation in Neurodegenerative Disease using Synthetic Proteins
使用合成蛋白质研究神经退行性疾病中的聚集
- 批准号:
10735475 - 财政年份:2019
- 资助金额:
$ 170.61万 - 项目类别:
Semi-synthetic a-Synuclein for Tracking Aggregation and Cell-to-Cell Transmission
用于跟踪聚集和细胞间传输的半合成α-突触核蛋白
- 批准号:
8421217 - 财政年份:2012
- 资助金额:
$ 170.61万 - 项目类别:
Semi-synthetic a-Synuclein for Tracking Aggregation and Cell-to-Cell Transmission
用于跟踪聚集和细胞间传输的半合成α-突触核蛋白
- 批准号:
8551784 - 财政年份:2012
- 资助金额:
$ 170.61万 - 项目类别:
Semi-synthetic a-Synuclein for Tracking Aggregation and Cell-to-Cell Transmission
用于跟踪聚集和细胞间传输的半合成α-突触核蛋白
- 批准号:
8900368 - 财政年份:2012
- 资助金额:
$ 170.61万 - 项目类别:
Semi-synthetic a-Synuclein for Tracking Aggregation and Cell-to-Cell Transmission
用于跟踪聚集和细胞间传输的半合成α-突触核蛋白
- 批准号:
8706997 - 财政年份:2012
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$ 170.61万 - 项目类别:
PEPTIDE THIOAMIDES AS FLUORESCENCE QUENCHING PROBES TO MONITOR PROTEIN DYNAMICS
肽硫代酰胺作为荧光淬灭探针来监测蛋白质动态
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8362581 - 财政年份:2011
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