ABNORMAL DJ-1 AND ALPHA-SYNUCLEIN IN NEURODEGENERATION

神经退行性变中的异常 DJ-1 和 α-突触核蛋白

• 批准号: 7616497
• 负责人: BENOIT I GIASSON
• 金额: $ 27.72万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7616497
• 关键词: Appearance; Binding; Biochemical; Biological; Breeding; Cell Death; Cell physiology; Cessation of life; Characteristics; Clinical; Complex; Cultured Cells; Defect; Disease; Etiology; Filament; Gene Mutation; Genes; Genetic; Glutamates; Human; Impairment; In Vitro; Intermediate Filaments; Knockout Mice; Knowledge; Lead; Lewy Bodies; Link; Midbrain structure; Movement Disorders; Mus; Mutation; Nerve Degeneration; Nervous System Heredodegenerative Disorders; Neurodegenerative Disorders; Neuroglia; Neurons; Oxidative Stress; Parkinson Disease; Pathologic Processes; Pathway interactions; Polymers; Process; Property; Proteins; Recombinants; Research Personnel; Role; SNCA gene; Stress; Therapeutic; Toxic effect; Transgenic Mice; alpha synuclein; disease characteristic; dopaminergic neuron; improved; insight; kindred; mutant; novel; polymerization; prevent; protein aggregation; stem; synuclein; tissue culture

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and it shares many common features, such as aberrant protein aggregation, with a broader spectrum of neurodegenerative diseases. Despite the knowledge that the loss of specific dopaminergic neurons in the midbrain is largely responsible for many of the clinical presentations of PD, there are significant unknowns about the mechanisms that lead to neuronal death. Genetic studies have identified new mutations and gene defects that can be responsible for disease. Although familial PD is relatively rare, these genetic findings have led to critical insights toward understanding the underlying cause of disease and they may begin to define important biological pathways involving the interaction of these gene products. The identification of mutations in the alpha-synuclein gene has revealed that this protein is the major component of disease-characteristic inclusions known as Lewy bodies. Furthermore, various types of alpha-synuclein filamentous inclusions have been shown to be involved in the etiology of many neurodegenerative diseases. However, there is evidence to suggest that the formation of these mature inclusions and/or the small oligomers, which can take the appearance of "spheres", can be involved in degeneration. In this proposal, the novel (E46K) mutation in alpha-synuclein, previously identified mutants and the wild-type protein will be studied in vitro, in tissue culture paradigms and in transgenic mice to investigate the molecular interactions and mechansims that lead to the aberrant polymerization of alpha-synuclein. The role of small polymeric "sphere" compared to mature filamentous inclusions in the disease process will be assessed. Defects in the DJ-1 gene have been linked to PD or PD-like disease, and an interactive pathogenic link between DJ-1 and alpha-synuclein, perhaps involving oxidative stress mechanisms, in normal and disease state will be evaluated. These findings should provide important information as to the directions for planning for effective therapeutic approaches.

帕金森氏病（PD）是最常见的神经退行性运动障碍，它具有许多常见特征，例如异常的蛋白质聚集，并具有更广泛的神经退行性疾病。尽管知道中脑中特定多巴胺能神经元的丧失主要是PD的许多临床表现，但关于导致神经元死亡的机制有很大的未知。遗传研究已经确定了可能导致疾病的新突变和基因缺陷。尽管家族性PD相对较少，但这些遗传发现导致了了解理解疾病根本原因的关键见解，它们可能开始定义重要 涉及这些基因产物相互作用的生物途径。 α-突触核蛋白基因突变的鉴定表明，该蛋白是疾病特征的夹杂物的主要组成部分，称为Lewy身体。此外，已证明各种类型的α-突触核蛋白丝状夹杂物与许多神经退行性疾病的病因有关。但是，有证据表明，这些成熟的夹杂物和/或小的低聚物的形成可能会涉及“球体”的外观。在该提案中，将在组织中研究α-突变核蛋白的新颖（E46K）突变，先前鉴定出的突变体和野生型蛋白 培养范例和转基因小鼠，研究导致α-核蛋白异常聚合的分子相互作用和机甲。与疾病过程中小型聚合物“球”与成熟丝状包裹体相比的作用将得到评估。 DJ-1基因中的缺陷与PD或PD样疾病有关，并且将评估DJ-1和α-核蛋白之间的相互作用致病联系，可能涉及正常和疾病状态下的氧化应激机制。这些发现应该 提供有关计划有效治疗方法的指示的重要信息。