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名退伍军人被诊断患有痴呆症， 在截至2020年的十年中，退伍军人中的阿尔茨海默病和其他痴呆症病例。 阿尔茨海默氏病（AD）、路易体痴呆（DLB）和帕金森氏病（PD）都是导致痴呆的原因 与蛋白质毒性有关的痴呆症;然后关键是要了解通过 有毒蛋白质的形成以及为什么它们从神经元中的去除是不充分的。蛋白毒性之间的联系， 代谢和自噬途径，去除有毒蛋白质，需要在分子水平上理解。 水平和神经退行性疾病的背景下。该提案侧重于一个未充分研究的途径， 在AD等散发性退行性疾病中具有重要意义。特别地，O-GlcNAc酰化的扰动， 作为一种营养感应途径，已在人类阿尔茨海默病（AD）脑中得到证实， O-GlcNAc酶（OGA）的抑制作用已显示在动物模型中有效抑制tau磷酸化。鉴于 由于增加O-GlcNAc水平的这些推定的有益作用，已经开始了临床试验以评估 增加这种翻译后修饰在治疗AD中的功效。无论是O- GlcNAc化途径是tau特异性的，或者也参与其他神经毒性蛋白，如α-突触核蛋白， 已在哺乳动物系统中进行了全面研究。我们是最早证明O-GlcNAc化是 参与哺乳动物系统中体内α-突触核蛋白的积累，并作为本研究的主要焦点。 提议为了支持这一观点，我们已经证明，抑制OGA可以增加自噬体和α- 原代神经元中的突触核蛋白积累和减弱的自噬通量。我们最近的出版物显示， 蛋白质O-GlcNAc化在PD患者中增加也强调了越来越需要了解 这一途径的分子调控。我们已经开发出了测试所需的遗传动物模型， 这一提议的总体假设是O-GlcNAc的持续增加导致α-突触核蛋白 在AD和DLB的发病机制中，AD和DLB是一种神经系统疾病，可导致AD的累积和神经功能障碍，从而促进AD和DLB的发病机制。 我们已经建立了一支强大的研究团队，拥有O-GlcNAc生物学的专业知识， O-GlcNAc修饰、自噬和组织特异性OGA缺陷的小鼠模型的光谱分析 和/或α-突触核蛋白过表达。本研究将：1）验证增加神经元O- GlcNAc水平破坏内源性α-突触核蛋白稳态并损害神经功能。 假设α-突触核蛋白以及自噬/内溶酶体蛋白O-GlcNAc修饰 有助于α-突触核蛋白积累，从而有助于神经变性。成功 这些研究的完成将确立O-GlcNAc化在调节α-突触核蛋白稳态中的作用， 神经毒性，并提供O-GlcNAc调节自噬的新机制的理解，这将指导 神经保护的策略。例如，可以想到的是，引入O-GlcNAc化位点肽 作为竞争性抑制剂的模拟物可能有益于防止有害的O-GlcNAc酰化，同时保持 有益的O-GlcNAc酰化。这项研究的成功可能会给受影响的退伍军人带来重大利益 这些疾病。