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: 6919448
• 负责人: BENOIT I GIASSON
• 金额: $ 26.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919448
• 关键词: Lewy body; Parkinson' s disease; alpha synuclein; family genetics; gene mutation; genetically modified animals; intermolecular interaction; laboratory mouse; molecular pathology; neural degeneration; oxidative stress; pathologic process; polymers; protein structure; protein structure function; recombinant proteins; tissue /cell 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.

帕金森病（PD）是最常见的神经退行性运动障碍，它与更广泛的神经退行性疾病有许多共同特征，如异常蛋白质聚集。尽管知道中脑中特异性多巴胺能神经元的丧失在很大程度上是PD的许多临床表现的原因，但关于导致神经元死亡的机制仍存在重大未知数。遗传学研究已经发现了可能导致疾病的新突变和基因缺陷。虽然家族性PD相对罕见，但这些遗传学发现为理解疾病的根本原因提供了重要见解，并且可能开始定义重要的 涉及这些基因产物相互作用的生物学途径。对α-突触核蛋白基因突变的鉴定表明，这种蛋白质是被称为路易体的疾病特征性包涵体的主要成分。此外，各种类型的α-突触核蛋白丝状包涵体已被证明参与许多神经退行性疾病的病因学。然而，有证据表明，这些成熟的内含物和/或小的寡聚体的形成，可以采取“球体”的外观，可以参与变性。在这个提议中，α-突触核蛋白中的新的（E46 K）突变，先前鉴定的突变体和野生型蛋白质将在体外，在组织中进行研究。 培养模式和转基因小鼠中研究导致α-突触核蛋白异常聚合的分子相互作用和机制。小聚合物“球”相比，成熟的丝状夹杂物在疾病过程中的作用将进行评估。DJ-1基因的缺陷与PD或PD样疾病有关，将评估DJ-1和α-突触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 为有效治疗方法的规划方向提供重要信息。