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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

基本信息

批准号：
9891116
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
项目类别：
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/9891116
关键词：
Address Affect Aging Alzheimer&apos s Disease Amino Acid Sequence Amyloid beta-Protein Attenuated Binding Biochemical Biological 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 Impairment 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 combat design experimental study extracellular improved in vivo inhibitor/antagonist insight multicatalytic endopeptidase complex mutant neurotransmission novel polyglutamine programs protein aminoacid sequence protein degradation proteostasis proteotoxicity receptor reconstitution

项目摘要

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.

蛋白酶体在生命过程中对蛋白质稳态和正常的神经元功能至关重要。这个新