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Uncovering the role of genetic MAPT variation in the pathogenesis of tauopathies: An early molecular phenotype

揭示 MAPT 遗传变异在 tau蛋白病发病机制中的作用：早期分子表型

基本信息

批准号：
9395425
负责人：
Julia Elise Gamache
金额：
$ 3.95万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-12 至 2020-07-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9395425
关键词：
Academia Address Affect Age Alzheimer&apos s Disease Aspartate Axon Biochemical Biological Markers Biology Brain CASP2 gene Chromosomes, Human, Pair 17 Cleaved cell Cognitive deficits Complex DNA Sequence Alteration Data Dendritic Spines Disease Engineering Event FTD with parkinsonism Family Foundations Frontotemporal Lobar Degenerations Future Gene Mutation Gene Transfer Techniques Genes Genetic Engineering Genetic Variation Goals Half-Life Heritability Human Impairment In Vitro Lead Link MAPT gene Measures Mediating Mentorship Messenger RNA Microtubules Mus Mutation Neurodegenerative Disorders Neurons Pathogenesis Pathogenicity Pathologic Pathologic Processes Pick Disease of the Brain Post-Translational Protein Processing Process Progressive Supranuclear Palsy Property Prosencephalon Protein Isoforms Proteins Public Health Regulation Research Role Science Series Students Synapses Tauopathies Testing Time Transgenes Transgenic Mice Variant Work base career disorder subtype effective therapy experimental study genetic variant in vivo insight molecular phenotype mouse model nervous system disorder novel postsynaptic pre-doctoral preclinical study presynaptic prevent tau Proteins tau aggregation tau conformation tau mutation transgene expression vector

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is one of a family of tauopathies, neurological disorders in which the microtubule- associated protein tau becomes abnormally regulated. Although heritable mutations in the tau gene (MAPT) cause a subset of familial tauopathies, it is not well understood how this genetic variation contributes to the deleterious effects of mutant tau in the brain. The Ashe lab has shown that tau with the P301L mutation, the most common MAPT mutation, mislocalizes within neurons from axons to dendritic spines, through a process involving proteolytic cleavage of tau at aspartate 314 (D314). The D314 tau cleavage product is associated with cognitive deficits in humans with Alzheimer’s, and inhibiting this cleavage event prevents neuronal mislocalization of P301L tau. Our preliminary data further show that, in six-week-old transgenic mice, cleavage of P301L tau leads to elevated tau levels in the brain, which can be reversed by rendering tau non-cleavable at D314. Multiple disease-linked MAPT mutations alter the global conformation of tau in a way similar to the P301L mutation, and can also cause subcellular mislocalization and elevation of tau protein levels. Therefore, we hypothesize that cleavage at D314 promotes missorting of tau harboring pathogenic mutations, and leads to elevated protein levels early in disease, an effect that can be reversed by inhibiting cleavage at D314. We will address this hypothesis with the following Specific Aims. Specific Aim 1 examines the effect of cleavage at D314 on the half-life and localization of P301L tau. Using precision transgenesis, we have developed novel mouse lines called the T-series, genetically equivalent in every way except for single mutations we have introduced into a tau transgene. In the brains of these mice engineered to express wild-type (WT) tau, P301L tau, and non-cleavable P301L tau, we will measure the in vivo half-life and subcellular localization of tau. Specific Aim 2 investigates the effect of cleavage at D314 on early protein levels of pathogenic mutant tau. We will generate T-series mice expressing cleavable or non-cleavable tau with known pathogenic mutations, including the G272V, V337M, and R406W mutations, and measure tau protein levels in the brain at six weeks. The experiments included in these aims will elucidate the relationship between localization and degradation of tau, and may identify a robust and early biomarker for preclinical studies of tauopathies, while also providing the field with novel mouse lines and vectors to further investigate tau biology in disease. Because there may be common mechanisms between familial and sporadic tauopathies, understanding the effects of MAPT mutations on the biochemical properties of tau may lead to more effective therapies for a broad range of incurable diseases.

项目总结/文摘