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Role of oligomeric alpha-synuclein in synucleinopathies

寡聚 α-突触核蛋白在突触核蛋白病中的作用

基本信息

批准号：
8453482
负责人：
Pamela J McLean
金额：
$ 32.38万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453482
关键词：
Acetylcysteine Affect Alzheimer&apos s Disease Biochemical Biological Assay Cell Death Cell physiology Cells Cytoplasm Dependovirus Deposition Development Disease Disease Progression Equilibrium Fluorescence Goals Health Human Huntington Disease Inherited Injection of therapeutic agent Intervention Lewy Bodies Lewy Body Dementia Life Link Location Membrane Mission Modification Molecular Chaperones Molecular Sieve Chromatography Mutation National Institute of Neurological Disorders and Stroke Nature Nerve Degeneration Neurodegenerative Disorders Neurons Parkinson Disease Parkinson&apos s Dementia Pathogenesis Play Population Prions Process Proteins Rattus Recombinant adeno-associated virus (rAAV)Role Spectrum Analysis Staging Substantia nigra structure System Techniques Testing Therapeutic Therapeutic Agents Toxic effect alpha synuclein cofactor dimer in vivo nervous system disorder novel novel strategies novel therapeutics prevent protein aggregate protein misfolding research study screening synuclein synucleinopathy therapeutic target tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The presence of insoluble protein aggregates is a pathological hallmark of neurodegenerative disorders such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease, Huntington's disease and prion protein disorders. In synucleinopathies such as PD and DLB, the Lewy body is the pathological protein aggregate that is found in the cytoplasm of susceptible neuronal populations. Lewy bodies are eosinophilic inclusions containing numerous aggregated proteins, including alpha-synuclein (1syn), which suggests a causative role for this protein in these disorders. Misfolding and aggregation of 1syn are thought to be critical cofactors linked to disease development. In particular, the accumulation of nonfibrillar dimers and oligomers of 1syn, which serve as intermediates for fibrillar Lewy body formation, is thought to cause neurodegeneration. Because oligomeric forms of 1syn are believed toxic to cells, an important therapeutic strategy will be to reduce oligomer formation or prevent it altogether. In this application we propose to study the role of oligomeric 1syn in synucleinopathies and examine how specific modifications affect toxicity and oligomer formation. To enable the direct study of 1syn oligomerization, we have applied novel strategies including protein complementation assays (PCAs), size exclusion chromatography (SEC) and fluorescence correlation spectroscopy (FCS) by which to identify and follow 1syn oligomer formation, thus providing a powerful toolbox of techniques with which to study manipulations affecting 1syn-induced toxicity. This application is divided into three coordinated and related aims that will characterize 1syn oligomers and investigate the role of 1syn oligomers in disease pathogenesis with a view to determining the effect of disease- related modifications and molecular chaperones on 1syn oligomer formation and subcellular location (aim 1 & 2). We also propose to recapitulate 1syn oligomerization in vivo via stereotactic injection of recombinant adeno-associated virus and examine the resulting toxicity and subcellular localization of 1syn oligomers in vivo, as well as the effect of molecular chaperone interventions identified in aim 2 (aim 3). We propose that this application offers an effective strategy by which to identify and modulate 1syn oligomer formation, and targets therapeutics to a pre-toxic stage of fibrillization, where rescue of the soluble, monomeric forms of 1syn can substantially impact disease progression. If successful, the experiments described will significantly advance the study of 1syn-induced toxicity and related oligomer formation, and contribute to the development of successful therapeutic strategies to treat PD and related disorders. Thus, this study is in accordance with the mission of NINDS - to reduce the burden of neurological disease.

描述（由申请人提供）：不溶性蛋白质聚集体的存在是神经变性疾病如帕金森病（PD）、路易体痴呆（DLB）、阿尔茨海默病、亨廷顿病和朊病毒蛋白质疾病的病理学标志。在突触核蛋白病如PD和DLB中，路易体是在易感神经元群体的细胞质中发现的病理性蛋白质聚集体。路易体是含有大量聚集蛋白的嗜酸性包涵体，包括α-突触核蛋白（1 syn），这表明该蛋白在这些疾病中的致病作用。1 syn的错误折叠和聚集被认为是与疾病发展相关的关键辅助因子。特别是，1 syn的非纤维状二聚体和寡聚体的积累，作为纤维状路易体形成的中间体，被认为是导致神经变性。因为1 syn的寡聚体形式被认为对细胞有毒，所以重要的治疗策略将是减少寡聚体形成或完全防止它。在本申请中，我们建议研究寡聚1 syn在突触核蛋白病中的作用，并研究特定修饰如何影响毒性和寡聚体形成。为了使1 syn寡聚化的直接研究，我们已经采用了新的策略，包括蛋白质互补分析（PCA），尺寸排阻色谱法（SEC）和荧光相关光谱（FCS），通过它来识别和跟踪1 syn寡聚体的形成，从而提供了一个功能强大的工具箱的技术，研究操作影响1 syn诱导的毒性。本申请分为三个协调且相关的目的，其将表征1 syn寡聚体并研究1 syn寡聚体在疾病发病机制中的作用，以期确定疾病相关修饰和分子伴侣对1 syn寡聚体形成和亚细胞定位的影响（目的1和2）。我们还建议通过立体定向注射重组腺相关病毒来概括体内1 syn寡聚化，并检查体内1 syn寡聚体的毒性和亚细胞定位，以及目标2（目标3）中确定的分子伴侣干预的效果。我们提出，该应用提供了一种有效的策略，通过该策略来识别和调节1 syn寡聚体形成，并将治疗剂靶向至凝血的毒性前阶段，其中1 syn的可溶性单体形式的拯救可以显著影响疾病进展。如果成功的话，所描述的实验将显著推进1 syn-induced毒性和相关寡聚体形成的研究，并有助于开发成功的治疗策略来治疗PD和相关疾病。因此，本研究符合NINDS的使命-减少神经系统疾病的负担。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Alpha-synuclein and tau: teammates in neurodegeneration?

DOI：
10.1186/1750-1326-9-43
发表时间：
2014-10-29
期刊：
Molecular neurodegeneration
影响因子：
15.1
作者：
Moussaud S;Jones DR;Moussaud-Lamodière EL;Delenclos M;Ross OA;McLean PJ
通讯作者：
McLean PJ

Ubiquitinylation of α-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5).

DOI：
10.1371/journal.pone.0014695
发表时间：
2011-02-16
期刊：
PloS one
影响因子：
3.7
作者：
Kalia LV;Kalia SK;Chau H;Lozano AM;Hyman BT;McLean PJ
通讯作者：
McLean PJ

Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.

DOI：
10.1371/journal.pone.0092098
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Dimant H;Zhu L;Kibuuka LN;Fan Z;Hyman BT;McLean PJ
通讯作者：
McLean PJ

α-Synuclein oligomers and clinical implications for Parkinson disease.

DOI：
10.1002/ana.23746
发表时间：
2013-02
期刊：
ANNALS OF NEUROLOGY
影响因子：
11.2
作者：
Kalia, Lorraine V.;Kalia, Suneil K.;McLean, Pamela J.;Lozano, Andres M.;Lang, Anthony E.
通讯作者：
Lang, Anthony E.

Drug targets from genetics: α-synuclein.