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: 10265330
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265330
• 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; Lead; 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; Pharmacology; Phenotype; Phosphorylation; Post-Translational Protein Processing; 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; cost; design; detection of nutrient; early onset; efficacy evaluation; genetic approach; in vivo; inhibitor/antagonist; interest; military veteran; mouse model; neurodegenerative phenotype; neuroprotection; neurotoxic; neurotoxicity; novel; novel therapeutics; overexpression; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; peptidomimetics; polymerization; preservation; prevent; protein transport; proteostasis; proteotoxicity; success; tau Proteins; tau aggregation; tau phosphorylation; 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21.8万名退伍军人被诊断为痴呆症，42.3万名新退伍军人 在截至2020年的十年中，退伍军人中出现了阿尔茨海默病和其他痴呆症病例。 阿尔茨海默病(AD)、路易体痴呆(DLB)和帕金森病(PD)都是致病因素 与蛋白毒性有关的痴呆症；然后关键是要通过 哪些有毒蛋白质形成，以及为什么从神经元中去除它们是不够的。蛋白毒性和蛋白质毒性之间的联系(S) 新陈代谢和去除有毒蛋白质的自噬途径需要从分子上理解。 在神经退行性疾病的情况下。这项建议关注的是一条未被充分研究的途径 感兴趣的是散发性退行性疾病，如AD。尤其是O-GlcN酰化的扰动， 作为一种营养感知途径，已被证明在人类阿尔茨海默病(AD)的大脑中具有抑制作用 在动物模型中，O-GlcNAcase(OGA)被证明能有效抑制tau的磷酸化。根据…… 这些增加O-GlcNAc水平的假定益处已经启动临床试验，以评估 药物增加这种翻译后修饰在治疗AD中的疗效。无论O- GlcN酰化途径是tau特有的，或者也与其他神经毒性蛋白，如α-突触核蛋白，没有 在哺乳动物系统中得到了充分的研究。我们是最早证明O-GlcN酰化的人之一 在哺乳动物体内参与α-突触核蛋白的积累，并作为这一研究的主要焦点 求婚。为了支持这一概念，我们已经证明，抑制OGA增加了自噬和α- 初级神经元中突触核蛋白的积累和减弱的自噬通量。我们最近的出版物显示 PD患者中蛋白质O-GlcN酰化增加也突显了越来越多的需要了解 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持续增加导致α-突触核蛋白 蓄积和神经功能障碍，从而促进AD和DLB的发病。 我们已经建立了一支强大的研究团队，拥有O-GlcNAc生物学、TAG-MASS尖端技术的专业知识 O-GlcNAc修饰、自噬和组织特异性OGA缺陷小鼠模型的光谱 和/或α-突触核蛋白过表达。这项研究将：1)检验假设，增加神经元的O- GlcNAc水平扰乱内源性α-突触核蛋白稳态并损害神经功能，2)测试 O-GlcNAc修饰α-突触核蛋白和自噬/内溶酶体蛋白的假说 有助于α-突触核蛋白的积累，从而促进神经退行性变。成功者 这些研究的完成将确立O-GlcN酰化在调节α-突触核蛋白动态平衡和 神经毒性，并为O-GlcNAc调节自噬提供了新的机制理解，这将指导 神经保护策略。例如，可以想象引入O-GlcN酰化位点肽 模拟物作为竞争性抑制剂可能有利于防止有害的O-GlcN酰化，同时保存 有益的O-GlcN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好处 这些疾病造成的。