Mechanisms Regulating Neuronal Specific Proteasomes in Neurodegeneration

神经变性中神经元特异性蛋白酶体的调节机制

• 批准号: 10328548
• 负责人: SETH S MARGOLIS
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328548
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Amino Acid Sequence; Amyloid beta-Protein; Attenuated; Binding; Biochemical; Brain; Brain Diseases; Calcium; Calcium Signaling; Cell membrane; Cell physiology; Cells; Cognition Disorders; Complex; Data; Defect; Detection; Disease; FOS gene; Glycoproteins; Goals; Health; High Prevalence; Human; Huntington Disease; In Vitro; Individual; Investigation; Knowledge; Life; Link; Maintenance; Measurement; Mediating; Membrane; Memory; Modality; Modeling; Molecular; Mus; Mutate; Nature; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Nuclear; Outcome; Paracrine Communication; Pathologic; Pathology; Patients; Peptide Receptor; Peptide Signal Sequences; Peptides; Permeability; Pharmacology; Physiological; Physiology; Process; Production; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Regulation; Research; Role; Signal Transduction; Specific qualifier value; Stress; Synapses; Synaptic plasticity; System; Testing; Ubiquitin; Work; age related; base; brain dysfunction; design; experimental study; extracellular; improved; in vivo; inhibitor; insight; multicatalytic endopeptidase complex; mutant; neurotransmission; novel; polyglutamine; programs; protein aminoacid sequence; protein degradation; proteostasis; proteotoxicity; receptor; reconstitution

Proteasomes are essential for protein homeostasis and proper neuronal function throughout life. This new application focuses on studying a newly discovered neuronal specific abundant proteasome complex and its link to neuronal function in health and aging related neurodegenerative disease. Based on extensive original findings, our central hypothesis is that neuronal activity promotes the degradation of newly synthesized proteins through a transmembrane-like proteasome complex in order to rapidly generate biologically meaningful peptides that are critical for normal nervous system function and appear protective against neurodegenerative processes. The rationale for the proposed research is that nothing is known about this new form of protein homeostasis and further understanding is critical in providing vital insight into neuronal functions mediated by protein degradation. Given the critical importance of protein degradation to human health, the long-range objective of the proposed research is to understand the regulation and function of this degradation program and to apply this knowledge to the detection and eventual treatment of cognitive disorders. Specifically: Aim 1. To identify and study molecular components required for NMP complex assembly and function, to test our hypothesis that a glycoprotein mediates transmembrane like association of the proteasome in the neuronal plasma membrane, which is critical for promoting NMP mediated peptide release and is in part controlled by the disease causing β–amyloid protein; Aim 2. To identify and study specific NMP peptide-receptor interactions relevant to neuronal signaling, to test our hypothesis that distinct amino acid sequences within NMP substrates are critical for NMP dependent degradation into unique peptides that activate NMDAR dependent neuronal signaling and that this interferes with Aβ induced pathologies; Aim 3. To investigate NMP relevance to neuronal physiology in healthy and diseased brains, to test our hypothesis that inhibition of NMP function affects neuronal physiology and is relevant to nervous system aging and neurodegenerative decline.

蛋白酶体对于蛋白质稳态和整个生命过程中的适当神经功能是必不可少的。这个新 本发明的应用集中于研究新发现的神经元特异性丰富蛋白酶体复合物及其 与健康和衰老相关的神经退行性疾病中的神经元功能有关。基于广泛的原始 研究结果，我们的中心假设是，神经元活动促进新合成的 蛋白质通过跨膜样蛋白酶体复合物，以快速生物生成 对正常神经系统功能至关重要的有意义的肽， 神经退化过程提出这项研究的理由是，对这种新的 蛋白质稳态的形式和进一步的理解是至关重要的，在提供重要的洞察神经元 由蛋白质降解介导的功能。考虑到蛋白质降解对人类的重要性， 健康，拟议研究的长期目标是了解这种调节和功能 退化程序，并将这些知识应用于检测和最终治疗认知 紊乱具体而言：目标1。鉴定和研究NMP复合物所需的分子组分 组装和功能，以验证我们的假设，即糖蛋白介导跨膜样协会 蛋白酶体的神经元质膜，这是至关重要的促进NMP介导的肽 释放，并部分由引起疾病的β-淀粉样蛋白控制;目的2.去识别和研究 与神经元信号传导相关的特定NMP肽-受体相互作用，以验证我们的假设，即 NMP底物内不同的氨基酸序列对于NMP依赖性降解成独特的 激活NMDAR依赖性神经元信号传导并干扰Aβ诱导的 病理学;目标3.研究NMP与健康和疾病患者神经元生理学的相关性 大脑，以检验我们的假设，即抑制NMP功能会影响神经元生理学，并与 神经系统老化和神经退行性衰退。