Mechanisms Regulating Neuronal Specific Proteasomes in Neurodegeneration

蛋白酶体对于蛋白质的动态平衡和整个生命过程中正常的神经元功能至关重要。这是一项新的 应用重点研究新发现的神经元特异性富含蛋白酶体复合体及其 与健康和衰老相关的神经退行性疾病的神经功能有关。基于广泛的原创 发现，我们的中心假设是神经元活动促进了新合成的 蛋白质通过跨膜样蛋白酶体复合体，以便在生物上快速生成 对正常神经系统功能至关重要并具有保护作用的有意义的多肽 神经退行性变过程。提出这项研究的理由是对这项新的研究一无所知 蛋白质动态平衡的形式和进一步的了解对于提供对神经元至关重要的洞察至关重要 由蛋白质降解所介导的功能。鉴于蛋白质降解对人类的关键重要性 健康，拟议研究的长期目标是了解这一调节和功能 退化计划，并将这一知识应用于认知障碍的检测和最终治疗 精神错乱。具体地说：目的1.鉴定和研究NMP复合体所需的分子组成 组装和功能，以检验我们的假设，即糖蛋白介导类似跨膜的结合 蛋白酶体在神经细胞质膜中的表达，这是促进NMP介导肽的关键 释放并部分受引起β-淀粉样蛋白的疾病控制；目的2.鉴定和研究 与神经元信号相关的特定NMP肽-受体相互作用，以检验我们的假设 NMP底物中不同的氨基酸序列对于NMP依赖降解为独特的 激活N-甲基-D-天冬氨酸受体依赖性神经元信号转导的多肽及其对β诱导的 病理学；目的3.研究NMP与健康人和疾病人神经生理学的相关性 来验证我们的假设，即抑制NMP功能会影响神经生理学，并与 神经系统老化和神经退行性衰退。

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.