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Isoform-dependent effects of tau phosphorylation in Alzheimer's disease

阿尔茨海默病中 tau 磷酸化的异构体依赖性效应

基本信息

批准号：
10745286
负责人：
Nima Nick Naseri
金额：
$ 7.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745286
关键词：
Acceleration Address Adult Affect Affinity Age Aging Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Behavior Binding Biological Assay Biology Biophysics Brain Cells Charge Chemicals Chemistry Complement Data Dementia Development Dimensions Disease Disease Progression Dissociation Doctor of Philosophy Embryo Embryonic Development FTD with parkinsonism Fetal Tissues Fluorescence Functional disorder Future Goals Grant Heterogeneity Hippocampus Impairment In Vitro Injections Lead Length Link MAPT gene Measures Microtubule Polymerization Microtubule Stabilization Microtubules Molecular Conformation Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Neurosciences Pathologic Pathology Pattern Phosphorylation Phosphorylation Site Play Positioning Attribute Protein Biosynthesis Protein Isoforms Proteins Research Personnel Resolution Role Science Site Solubility Spectrum Analysis Structure Tauopathies Techniques Testing Total Internal Reflection Fluorescent Training Transgenic Mice Tubulin Tubulin Interaction age related aging brain biophysical techniques chemical synthesis driving force experimental study fetal gain of function hyperphosphorylated tau in vivo insight mouse model nervous system disorder neuropathology novel peptide chemical synthesis post-doctoral training proteostasis single molecule single-molecule FRET skills tau Proteins tau aggregation tau function tau mutation tau-1 tool

项目摘要

Neuropathology of the microtubule-associated protein tau is central to numerous devastating neurological disorders termed tauopathies, including Alzheimer's disease (AD). Tau promotes microtubule (MT) polymerization and stability via its interaction with tubulin, regulated by phosphorylation to tau in multiple domains. Six major tau isoforms are alternatively spliced in an age-dependent manner. While FTDP-17-causing mutations in tau show isoform-dependent effects on aggregation and microtubule stabilization, there are no tau mutations linked to AD. Meanwhile, isoform-dependent effects of phosphorylation to tau remain unexplored. Interestingly, I discovered that numerous AD-relevant phospho-tau (pTau) sites are also phosphorylated during normal embryonic development, and then decrease over age. Why are specific pTau sites, which are correlated with disease, also expressed during normal development? The parallel between the developmental and pathological states suggests that understanding the function of pTau during development would elucidate the mechanism(s) underlying tau pathology in AD. My preliminary data indicate that i) numerous AD-relevant pTau sites are expressed in normal embryonic mouse brains, ii) pTau is soluble and likely functional in fetal tissue, iii) phosphorylation at sites T231, S235 and S262 impair MT polymerization by the fetal tau isoform but not an adult isoform, and iv) these same pTau sites accelerate aggregation of the adult isoform over the fetal isoform. Recent evidence demonstrates that tau initiates nucleation of MT polymerization. Based on my preliminary data, ! propose that tau phosphorylation has isoform-dependent effects, in which specific pTau sites are detrimental to adult isoforms in an aging brain but functional in the fetal isoform in developing brains. I will explore two aims which will provide critical insight to understanding the effects of tau phosphorylation in each isoform. In Aim 1, I will determine the relationship between the interaction between pTau with both soluble tubulin and stabilized MTs in each isoform. In Aim 2, I will test for the relationship between pTau sites which cause tau to dissociate from MTs with those that accelerate its aggregation and/or seeding activity. Importantly, our lab has uniquely synthesized full-length tau with genuine chemical phosphorylation at sites T231, S235 and S262 for these studies. These experiments will be tested using multiple platforms including these chemically-synthesized proteins, high-resolution single-molecule techniques (single-molecule FRET, fluorescence correlative spectroscopy, and time-lapse TIRF microscopy), and injection of semi-synthesized proteins into mouse brains. The investigator has 6+ years of expertise in working with the biological assays and mouse models described here, and the sponsor and collaborators will guide training in the described chemical and biophysical techniques. I anticipate that my findings will elucidate the function of tau in developing neurons, and will provide insight into mechanisms of pathological tau hyperphosphorylation across numerous tauopathies including AD.

微管相关蛋白tau的神经病理学是许多毁灭性神经系统疾病的核心