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（由适用提供）：帕金森氏病（PD）是最常见的运动障碍，仅在北美影响了100万人，并导致生活质量和功能能力的阴险降低。 PD的标志是蛋白A-突触核蛋白的神经元细胞质内包含物的大脑积累，但是在神经退行性疾病的范围中观察到α-突触核蛋白脑聚集体的存在，包括与Lewy身体的痴呆症。几个发现表明，α-突触核蛋白淀粉样蛋白病理可能会通过蛋白质会议机制的自我测定改变在疾病进展过程中传播，但是，在我们的数据支持的情况下，其他替代性和/或协同生物学机制也可能导致α-核蛋白病理学的进展。从治疗方面，确定α-突触核蛋白聚集在疾病中的相对重要性，机制和生理后果至关重要。该提议提出了两个主要的特定目的，以告知α-突触核蛋白引起的疾病和传播：1）使用野生型和疾病，导致突变形式的 α-突触核蛋白具有独特的聚集特性，我们将直接研究A-突触核蛋白聚集可以在中枢神经系统内传播，并从具有特定概念特征的外周内传播。 2）我们将评估替代生物学机制的重要性，包括蛋白质网络稳态的扰动，神经元中间细丝完整性，神经毒性和与年龄相关的诱导和传播α-核蛋白病理学的诱导和传播与外源性A-核蛋白挑战的诱导和传播。这些研究将为α-突触核蛋白聚集在PD疾病进展中的机制和参与提供关键见解，目的是指导新疗法的发展。