Mechanisms of Aggregated Alpha-Synuclein Induction and Progression

聚集的 α-突触核蛋白诱导和进展的机制

基本信息

批准号：
9326346
负责人：
BENOIT I GIASSON
金额：
$ 32.27万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326346
关键词：
Affect Age-Years Aging Amyloid Autopsy Biological Brain Brain Stem Brain Tissue Transplantation Cerebrum Characteristics Cytoplasmic Inclusion Data Development Disease Disease Progression Disease model Embryo Etiology Future Genes Genetic study Goals Homeostasis In Vitro Injectable Injection of therapeutic agent Intermediate Filaments Lead Lewy Bodies Lewy Body Dementia Mediating Missense Mutation Molecular Molecular Conformation Movement Disorders Mus Neuraxis Neurites Neurodegenerative Disorders Neuronal Dysfunction Neurons North America Parkinson Disease Pathologic Pathology Patients Peripheral Peripheral Nerves Peripheral Nervous System Physiological Polymers Population Property Protein Conformation Proteins Proteome Quality of life Reporting Research Project Grants Role Seminal Study models Suggestion Testing Therapeutic Tissue Grafts Transgenic Mice age related alpha synuclein amyloid pathology conformer cross reactivity dopaminergic neuron early onset immunoreactivity in vivo insight molecular mass mouse model mutant neurofilament neurotoxicity novel novel therapeutic intervention novel therapeutics permissiveness prion-like protein misfolding proteostasis public health relevance therapeutic target tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Parkinson disease (PD) is the most common movement disorder affecting over one million people in North America alone and results in an insidious reduction in the quality of life and ability to function. A hallmark of PD is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein a-synuclein, but the presence of α-synuclein brain aggregates is observed in a spectrum of neurodegenerative diseases, including dementia with Lewy body. Several findings suggest that α-synuclein amyloid pathology may spread during disease progression by a self-templating alteration in protein conformation mechanism, however other alternative and/or synergistic biological mechanisms, as supported by our data, could also lead to progression of α-synuclein pathology. From a therapeutic aspect it is critical to determine the relative importance, mechanisms and physiological consequences of the spread of α-synuclein aggregation in disease. It this proposal, two major specific aims are proposed to inform on α-synuclein induced and spread of disease: 1) Using both wild-type and disease causing mutant forms of α-synuclein with unique aggregation properties, we will directly investigated that a-synuclein aggregation can spread within the central nervous system and from the periphery with specific conformational characteristics. 2) We will assess the importance of alternative biological mechanisms including perturbation of the protein network homeostasis, neuronal intermediate filament integrity, neurotoxicity and age-related changes in the induction and propagation of α-synuclein pathology by exogenous a-synuclein challenges. These studies will provide critical insights on the mechanisms and the involvement of α-synuclein aggregation in PD disease progression with the objective of guiding the development of novel therapeutics.

描述（由申请人提供）：帕金森病 (PD) 是最常见的运动障碍，仅在北美就影响了超过一百万人，并导致生活质量和功能能力的潜在下降。 PD 的一个标志是大脑。由蛋白质α-突触核蛋白组成的神经元细胞质内含物的积累，但在一系列神经退行性疾病中观察到α-突触核蛋白脑聚集物的存在，包括路易体痴呆。 α-突触核蛋白淀粉样蛋白病理学可能在疾病进展过程中通过蛋白质构象机制的自我模板改变而传播，然而，正如我们的数据所支持的，其他替代和/或协同生物机制也可能导致 α-突触核蛋白病理学的进展。治疗方面，确定 α-突触核蛋白聚集在疾病中传播的相对重要性、机制和生理后果至关重要。根据该提议，提出了两个主要具体目标来了解 α-突触核蛋白诱导和传播。疾病：1)同时使用野生型和致病突变型 α-突触核蛋白具有独特的聚集特性，我们将直接研究α-突触核蛋白聚集可以在中枢神经系统内以及具有特定构象特征的外周扩散2)我们将评估替代生物机制的重要性，包括蛋白质网络的扰动。外源性α-突触核蛋白挑战诱导和传播α-突触核蛋白病理学中的稳态、神经元中间丝完整性、神经毒性和年龄相关变化。研究将为 α-突触核蛋白聚集在 PD 疾病进展中的机制和参与提供重要见解，目的是指导新疗法的开发。