O-GlcNAc in protein homeostasis in the context of PD, AD and DLB

PD、AD 和 DLB 背景下 O-GlcNAc 在蛋白质稳态中的作用

• 批准号: 10554302
• 负责人: Jianhua Zhang
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554302
• 关键词: Adolescent; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; American; Animal Genetics; Animal Model; Attenuated; Autophagocytosis; Autophagosome; Biology; Brain; Brain Diseases; Chronic; Clinical Trials; Degenerative Disorder; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Excision; Foundations; Homeostasis; Human; Impairment; In Vitro; Intervention; Learning; Light; Link; Lysosomes; Mass Spectrum Analysis; Membrane; Memory; Metabolic; Metabolism; Modification; Molecular; Mus; Mutation; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Polymers; Post-Translational Protein Processing; Protein Dynamics; Proteins; Proteome; Proteomics; Publications; Rattus; Regulation; Reporting; Research; Role; Site; System; Techniques; Testing; Tissue Model; Toxic effect; Transgenic Mice; Tubulin; Veterans; Work; aged; aging brain; alpha synuclein; comparison control; cost; design; detection of nutrient; early onset; efficacy evaluation; genetic approach; in vivo; inhibitor; interest; military veteran; mouse model; neurodegenerative phenotype; neuroprotection; neurotoxic; neurotoxicity; novel; novel therapeutics; overexpression; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; peptidomimetics; pharmacologic; polymerization; preservation; prevent; protein transport; proteostasis; proteotoxicity; success; tau Proteins; tau aggregation; tau-1; trafficking

It is estimated that approximately 218,000 Veterans were diagnosed with dementia in 2017, and 423,000 new cases of Alzheimer's disease and other dementias among military veterans in the decade ending in 2020. Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB) and Parkinson's disease (PD) are all contributors to dementia which are associated with proteotoxicity; it is then critical to understand the mechanisms through which toxic proteins form and why their removal from neurons is inadequate. The link(s) between proteotoxicity, metabolism and the autophagy pathway, which removes toxic proteins, needs to be understood at a molecular level and in the context of neurodegenerative disease. This proposal focuses on an understudied pathway that is of interest in the sporadic degenerative diseases such as AD. In particular, perturbation of O-GlcNAcylation, as a nutrient sensing pathway, has been demonstrated in human Alzheimer's disease (AD) brains, and inhibition of O-GlcNAcase (OGA) has been shown effective in inhibiting tau phosphorylation in animal models. In light of these putative beneficial effects of increasing O-GlcNAc levels, clinical trials have been initiated to evaluate the efficacy of pharmacologically increasing this post-translational modification in treating AD. Whether the O- GlcNAcylation pathway is tau specific or also engages other neurotoxic proteins, such as α-synuclein, has not been fully investigated in a mammalian system. We are among the first to demonstrate that O-GlcNAcylation is involved in α-synuclein accumulation in vivo in mammalian systems and serves as the principal focus of this proposal. In support of this concept, we have shown that inhibition of OGA increased autophagosomal and α- synuclein accumulation and attenuated autophagic flux in primary neurons. Our recent publication showing that that protein O-GlcNAcylation is increased in PD patients also underlines the growing need to understand the molecular regulation of this pathway. We have already developed the genetic animal models needed to test the overall hypothesis of this proposal that a sustained increase in O-GlcNAc causes α-synuclein accumulation and neurological dysfunction, thereby contributing to the pathogenesis of AD and DLB. We have built a strong research team with expertise in O-GlcNAc biology, cutting-edge techniques in tag-mass spectrometry of the O-GlcNAc modification, autophagy, and mouse models of tissue specific OGA deficiencies and/or with α-synuclein overexpression. This study will: 1) Test the hypotheses that increasing neuronal O- GlcNAc levels disrupts endogenous α-synuclein homeostasis and impairs neurological function, 2) Test the hypothesis that O-GlcNAc modification of α-synuclein as well as autophagy/endolysosomal proteins both contribute to α-synuclein accumulation and thereby contributing to neurodegeneration. The successful completion of these studies will establish a role for O-GlcNAcylation in regulating α-synuclein homeostasis and neurotoxicity, and provide new mechanistic understanding of O-GlcNAc regulation of autophagy, which will guide strategies for neuroprotection. For example, it is conceivable that introducing O-GlcNAcylation site peptide mimetic as competitive inhibitors may be beneficial to prevent detrimental O-GlcNAcylation while preserving beneficial O-GlcNAcylation. Success of this study may bring significant benefit to the Veterans who are affected by these diseases.

据估计，2017年约有218,000名退伍军人被诊断出患有痴呆症，423,000名新的 在2020年结束的十年中，军事退伍军人中阿尔茨海默氏病和其他痴呆症病例。 阿尔茨海默氏病（AD），有路易尸体（DLB）和帕金森氏病（PD）都是贡献者 与蛋白毒性相关的痴呆症；然后，了解通过的机制至关重要 哪种有毒蛋白会形成，为什么它们从神经元中移除不足。蛋白毒性之间的链接， 新陈代谢和去除有毒蛋白的自噬途径需要在分子上理解 水平和神经退行性疾病的背景。该提议着重于一种理解的途径 对零星的退化性疾病（例如AD）很感兴趣。特别是，O-Glcnacylation的扰动， 作为一种营养感应途径，在人类阿尔茨海默氏病（AD）大脑中已证明 O-Glcnacase（OGA）的of已显示在动物模型中抑制tau磷酸化方面有效。鉴于 这些假定的有益作用增加了O-GLCNAC水平，已开始临床试验来评估 药物在治疗AD方面的这种翻译后修饰的有效性。是否O- Glcnacylation途径是特异性的，或者也参与其他神经毒性蛋白，例如α-核蛋白，尚未 我们是第一个证明O-Glcnacylation的人之一 参与哺乳动物系统中体内α-核蛋白积累，并作为主要重点 提议。为了支持这一概念，我们已经表明，抑制OGA增加了自噬体和α- 突触核蛋白的积累和原发性神经元中的自噬通量减弱。我们最近的出版物显示 PD患者的蛋白质O-Glcnacylation增加也强调了了解 该途径的分子调节。我们已经开发了测试所需的遗传动物模型 该提议的总体假设是，O-GLCNAC持续增加会导致α-突触核蛋白 积累和神经功能障碍，从而导致AD和DLB的发病机理。 我们已经建立了一个具有O-GLCNAC生物学专业知识的强大研究团队 O-GLCNAC修饰，自噬和小鼠特异性OGA缺陷模型的光谱法 和/或α-突触核蛋白过表达。这项研究将：1）测试增加神经元O-的假设 GlcNAC水平破坏内源性α-突触核蛋白稳态并损害神经功能，2）测试 假设O-GLCNAC修饰α-突触核蛋白以及自噬/内溶性蛋白 有助于α-核蛋白积累，从而有助于神经退行性。成功 这些研究的完成将确定O-Glcnacylation在确定α-突触核蛋白稳态和 神经毒性，并提供对O-GLCNAC自噬调节的新机械理解，这将指导 神经保护策略。例如，可以想象引入O-Glcnacylation网站Pepperide 模拟竞争抑制剂可能有益于防止有害的O-Glcnacylation保存 有益的O-Glcnacylation。这项研究的成功可能会给受影响的退伍军人带来巨大的好处 通过这些疾病。