DJ-1 and its interactions with Parkin and Alpha-Synuclein

DJ-1 及其与 Parkin 和 Alpha-Synuclein 的相互作用

• 批准号: 7328670
• 负责人: Chenere Pierce Ramsey
• 金额: $ 4.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7328670
• 关键词: Affect; Age; Age of Onset; Amyotrophic Lateral Sclerosis; Behavior; Biochemical Pathway; Biological; Biological Process; Bradykinesia; Brain region; Cell Culture System; Cell Death; Cell Survival; Cell model; Cell physiology; Cells; Cultured Cells; Data; Dementia; Development; Diagnosis; Dimerization; Disease; Gene Mutation; Genetic; Genetic Crosses; Genetic Transcription; Goals; Human; In Vitro; Knockout Mice; Laboratories; Lead; Link; Measures; Modification; Motor; Movement Disorders; Mus; Muscle Rigidity; Mutant Strains Mice; Mutation; Nature; Nerve Degeneration; Neurons; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Population; Post-Translational Protein Processing; Predisposition; Process; Progressive Disease; Property; Proteins; Regulation; Reporting; Rest Tremor; Risk; Role; Site-Directed Mutagenesis; Solubility; Stimulus; Substantia nigra structure; Testing; Transgenic Organisms; Translations; Wild Type Mouse; age related; aging population; alpha synuclein; base; brain tissue; disease-causing mutation; human disease; in vivo; insight; mouse model; mutant; novel; parkin gene/protein; parkin protein; pars compacta; research study; synuclein

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting 1-4% of the population above the age of 65. To date, the cause for the majority of patients with PD is unknown and the cellular pathways implicated are ill-defined. The risk for PD diagnosis increases with age. Thus, with an increasingly aging population, it becomes necessary to better understand PD pathogenesis. Due to genetic defects, a paucity of a protein called DJ-1 can lead to Parkinson's disease in some patients. The overall goal of the project is to identify the cellular role(s) of DJ-1 and its relationships to other proteins, Parkin and alpha-Synuclein, which are also directly implicated in Parkinson's disease. In this proposal, the ability of DJ-1 to regulate Parkin expression and the mechanism(s) involved in the process will be assessed. The biological activities of DJ-1 and effects of the loss thereof due to disease-causing mutations will be investigated. It also is proposed that novel modifications of DJ-1 will be identified, as they may provide insights into the function of DJ-1. The ability of DJ-1 to suppress alpha-Synuclein aggregation, which is involved in pathobiology of Parkinson's disease, will also be assessed in vivo. These studies will be conducted by using cell culture systems and transgenic mouse models of the human disease. The completion of these studies will provide a better understanding of the biological function of DJ-1 and its interplay with other specific proteins such as Parkin and alpha-Synuclein in defining biological pathways involved in the pathobiology of PD.

描述(申请人提供)：帕金森病(PD)是最常见的神经退行性运动障碍，影响1-4%的65岁以上人口。到目前为止，大多数帕金森病患者的病因尚不清楚，所涉及的细胞通路也不明确。随着年龄的增长，诊断为帕金森病的风险增加。因此，随着人口老龄化的日益加剧，有必要更好地了解PD的发病机制。由于遗传缺陷，一种名为DJ-1的蛋白质的缺乏可能会导致某些患者患上帕金森氏症。该项目的总体目标是确定DJ-1的细胞角色(S)及其与其他蛋白质的关系，Parkin和α-突触核蛋白也直接与帕金森氏症有关。在这项提案中，将评估DJ-1调节Parkin表达的能力和参与这一过程的机制(S)。将调查DJ-1的生物学活性以及由于致病突变而导致其丢失的影响。还建议确定DJ-1的新修饰，因为它们可能为DJ-1的功能提供洞察力。DJ-1抑制α-突触核蛋白聚集的能力也将在体内进行评估，这与帕金森病的病理生物学有关。这些研究将通过使用细胞培养系统和人类疾病的转基因小鼠模型进行。这些研究的完成将有助于更好地了解DJ-1的生物学功能，以及它与其他特定蛋白(如Parkin和α-突触核蛋白)的相互作用，从而确定参与PD病理生物学的生物学途径。