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Prion and non-prion induction mechanisms of alpha-synuclein pathology

α-突触核蛋白病理学的朊病毒和非朊病毒诱导机制

基本信息

批准号：
10214707
负责人：
DAVID R BORCHELT
金额：
$ 37.96万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214707
关键词：
Applications Grants Biochemical Biological Biological Products Brain Cell Culture Techniques Cell Death Cell physiology Cerebrum Characteristics Complex Data Disease Disease Progression Etiology Exhibits Experimental Models Genes Genetic study Human Immune Impairment Injections Knockout Mice Lewy Bodies Lewy Body Dementia Lewy neurites Link Medical Microglia Missense Mutation Molecular Conformation Multiple System Atrophy Mus Nature Nerve Tissue Nervous System Heredodegenerative Disorders Nervous system structure Neurodegenerative Disorders Neuroglia Neurons Oligodendroglia Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Play Prion Diseases Prions Procedures Process Property Proteins Reporting Research Personnel Risk Role Serial Passage Severity of illness Spinal Cord Spinal Injections System Tissues Transgenic Mice Wild Type Mouse alpha synuclein cell type chemical property disease transmission disorder risk early onset experience extracellular human disease human tissue insight motor impairment non-prion prion-like protein complex proteostasis social implication synuclein synucleinopathy transmission process uptake white matter

项目摘要

The presence of a-synuclein brain aggregates are a hallmark of a spectrum of neurodegenerative disorders, including Parkinson disease, Lewy body dementia and multiple system atrophy, and are associated with disease severity. Several studies suggest that this a-synuclein pathology may spread during disease progression by a self-templating mechanism and that nervous tissue containing aggregated a-synuclein could be a risk for disease transmission similar to prion disease. However, we recently demonstared that a non-- synuclein factor enriched in central nervous tissue-derived white matter is sufficient to induce the progressive formation of a-synuclein inclusion pathology that can mimic prion-like transmission of a-synuclein pathology. These observations suggest the presence of a yet unidentified factor that can trigger a-synucleinopathy, similar to protein X, a putative auxiliary factor in prionopathies. Furthermore, this factor may have a pathogenic role in human disease. To resolve critical issues at the core of whether synucleinopathies should be re-classified as prion disorders and to elucidate mechanisms involved in disease progression we propose the following aims: 1) characterize the biochemical properties of the non-a-synuclein component that can trigger the progressive formation of a-synuclein, 2) determine whether a-synuclein aggregates can truely exhibit properties expected of classical prions, and 3) determine the relative prion-like transmission properties of central nervous tissue from patients with multiple system atrophy and Lewy body dementia, two phenotypically distinctive a-synucleinopathies. These highly integrated aims will provide important mechanistic and biologically relevant insights into the mechanisms and risk of pathology transmission from tissues containing a-synucleinopathies.

a-突触核蛋白脑聚集物的存在是a-突触核蛋白脑聚集物的标志