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Towards Understanding the Initiating Role of Truncated Alpha-Synuclein in Neurodegeneration

理解截短的 α-突触核蛋白在神经退行性变中的起始作用

基本信息

批准号：
9759501
负责人：
Zachary A Sorrentino
金额：
$ 3.92万
依托单位：
UNIVERSITY OF FLORIDA
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：
2019-05-16 至 2024-05-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759501
关键词：
Affect Aging Alzheimer&apos s Disease Animal Model Animals Appearance Biochemical Biological Assay Cell Culture Techniques Cell Death Cell model Cells Cerebrum Characteristics Data Dementia Detection Disease Disease Progression Disease model Etiology Gene Transfer Techniques Goals Human Impairment In Vitro Inclusion Bodies Individual Inflammation Inherited Injections Investigation Length Lewy Bodies Lewy Body Dementia Light Modeling Molecular Morphology Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Physiological Post-Translational Protein Processing Prevention Process Property Proteins Recombinant adeno-associated virus (rAAV)Reporting Role Severities Tauopathies Testing Time Toxic effect Transgenic Animals Viral Work alpha synuclein combat comparative economic impact experimental study in vivo mouse model mutant new therapeutic target overexpression prevent prion-like recruit synucleinopathy tau Proteins tau aggregation therapeutic target

项目摘要

Project Summary/Abstract: Dementia afflicts 47 million individuals worldwide and has an economic impact of more than $800 billion; neurodegenerative diseases for which no disease modifying therapies exist are the most common etiology. α-synuclein (αS) aggregates into toxic fibrils in multiple neurodegenerative diseases where the fibrils form characteristic inclusions implicated in disease progression. Mechanisms through which initial αS fibrils form is unclear, and yet halting their appearance is key to preventing disease. Carboxy-terminal truncation (C-truncation) of αS may be crucial in disease pathogenesis, as it has been repeatedly shown in- vitro that C-truncated αS spontaneously assembles into fibrils more readily than full-length αS. Proteolytic formation of these truncated species, possibly promoted by aging associated lysosomal impairment, may be key to initial pathology formation in disease. Additionally, C-truncated αS is increased in disease suggesting a pathologic role, where 15-20% of αS in inclusions is truncated. Therefore, The Aims of this project are to characterize naturally formed C-truncated species of αS for their ability to aggregate into pathologic fibrils and stimulate synergistic formation of αS and tau pathology in-vivo. Specific Aim one: Investigate the propensity of physiologic C-terminally truncated αS to pathologically aggregate in-vitro and in cellular models of synucleinopathy and tauopathy. Herein, I will characterize the aggregation propensity of naturally formed C-truncated αS both in-vitro and in-vivo using well characterized models. My working hypothesis is that truncated forms of αS will aggregate readily and synergistically induce full-length αS and tau fibril formation. These results will elucidate molecular mechanisms of aggregation and set the stage for further in-vivo work. Specific Aim two: Determine the ability of physiologic C-terminally truncated αS to initiate pathology in mouse models of synucleinopathy and tauopathy utilizing cerebral fibril injection and recombinant adeno associated virus (rAAV). Viral overexpression of familial aggregation prone αS mutants in mice results in neurodegenerative features used to model disease. Additionally, injection of preformed αS fibrils has been found to hasten progression of the disease in transgenic animals. My working hypothesis is that injection of truncated αS fibrils, and conversely rAAV overexpression of truncated αS in mice will initiate αS and tau pathology. These experiments will uncover pathogenic roles for αS truncation in neurodegenerative diseases.

项目摘要/摘要：全球有4700万人患有痴呆症，其经济影响为