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Structure and function of mammalian CPEB2 aggregates in normal and AD brain

正常和 AD 脑中哺乳动物 CPEB2 聚集体的结构和功能

基本信息

批准号：
10328953
负责人：
Kausik Si
金额：
$ 45.19万
依托单位：
STOWERS INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328953
关键词：
Acute Address Adult Alzheimer&apos s Disease Amyloid Amyloid beta-42 Animals Aplysia Autopsy Biochemical Biological Biological Assay Brain CPE-binding protein Cell physiology Cells Clinical Trials Complex Cre lox recombination system Cryoelectron Microscopy Cytoplasmic Structures Cytoplasmic Tail Development Disease Drosophila genus Excision Failure Family Family member Foundations Future Genetic Translation Human Hydrophobicity Immune In Vitro Invertebrates Knowledge Length Light Link Lobe Mammals Memory Memory Loss Memory impairment Methods Modeling Molecular Mus Nervous system structure Neurodegenerative Disorders Neurons Pathologic Polyribosomes Process Property Prosencephalon Protein Family Protein Isoforms Proteins Proteome RANK protein RNA Binding RNA-Binding Proteins Resistance Resolution Source Structure Synapses System TEV protease Techniques Tertiary Protein Structure Testing Thinking Tissues Training Translations base brain tissue effective therapy experience human subject hydrophilicity improved in vivo insight long term memory memory consolidation memory recall non-Native preclinical trial prion-like protein aggregation proteostasis standard of care tau Proteins

项目摘要

Project Summary The aggregate failure of pre-clinical and clinical trials in AD has demonstrated that an improved fundamental understanding of memory and how the molecular components of memory are altered in the AD disease process is necessary to develop effective treatment. The broad objective of the project is to identify the biochemical substrates of long-lasting memories in mammals. The current proposal focuses on a family of RNA-binding, cytoplasmic polyadenylation element binding protein (CPEB), that stabilizes memory in invertebrates and mice. Remarkably, CPEB family protein forms non-disease-causing amyloidogenic aggregates and aggregation of CPEB is necessary to stabilize memory. As amyloids are typically linked to disease states, the question remains how similarly structured Aβ42 or Tau proteins can have opposing effects on memory. Therefore, to develop a better understanding of the relationship between amyloids that support memory and amyloids that disrupt memory, we will use a variety of techniques to solve the structure and function of the CPEB family members, CPEB2 and CPEB3, in human and mice. In Aim 1, we will use cryo- electron microscopy to solve the structure of CPEB aggregates from fresh human frontotemporal lobe tissue collected from 25-50-year-old human subjects undergoing tissue removal under the standard of care for their disease. These tissues would have been otherwise discarded. In Aim 2, mice lacking the ability to form aggregates of CPEB2 and CPEB3 will be trained and tested in a one-trial inhibitory avoidance task to assay their ability to form, maintain, and recall memory. In Aim 2 we will also investigate the consequence of CPEB2 and CPEB3 aggregation in translation of mRNA encoding synaptic proteins. The results would be the first to provide direct structural analysis of a functional amyloid linked to memory in mammals, the structural distinctions, if any, between functional and toxic amyloid in the human brain, and precisely link CPEB2 and CPEB3 aggregation and activity to animals’ ability to form or stabilize memory. This knowledge would provide the foundation to investigate in the future how toxic amyloids of Aβ42 or Tau specifically perturb memory.

项目总结