Hsp70/DnaJ interface as a drug target for Alzheimer's disease and TBI

Hsp70/DnaJ 界面作为阿尔茨海默病和 TBI 的药物靶点

• 批准号: 8764624
• 负责人: Chad A. Dickey
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764624
• 关键词: ATP phosphohydrolase; Alzheimer' s Disease; Behavior; Binding; Biology; Brain; Cessation of life; Chemical Modifier; Chemicals; Clinical Trials; Data; Disease; Drug Targeting; Epidemic; Family; Genetic; Goals; Heat-Shock Proteins 70; Lead; Link; Long-Term Effects; Mediating; Metabolism; Microtubules; Molecular Chaperones; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pharmaceutical Preparations; Phenocopy; Population; Process; Protein Family; Protein Isoforms; Proteins; Pump; Regulation; Slice; Specificity; Subfamily lentivirinae; Tauopathies; Testing; Therapeutic; Transgenic Mice; Traumatic Brain Injury; Triage; Variant; Veterans; combat; design; drug development; heat-shock proteins 40; in vivo; killings; knock-down; member; mutant; neurofibrillary tangle formation; new therapeutic target; novel therapeutics; tau Proteins; therapeutic target; tool

DESCRIPTION (provided by applicant): Accumulation of the microtubule associated protein tau is associated with neuronal death in Alzheimer's disease (AD), Parkinson's disease and traumatic brain injury (TBI). Therefore tau is a tractable therapeutic target for each of these diseases. The chaperone family of proteins, and in particular the heat shock protein 70 family, is critical for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is strongly associated with granulovacuolar degenerating bodies (GVDs), which are major tau-associated pathological entities in AD neurons that are linked to autophagic clearance mechanisms. Co-localization studies have also shown that Hsp73 associates with accumulated tau in the brain. However, the actual mechanisms involving the Hsp70 family with tau biology have been challenging to define. Hsp70 proteins can either promote tau clearance or functionally preserve it. Recently, we have begun to elucidate the reason for this dichotomy. We have found that Hsp70 proteins act to seek out, identify and hold onto tau, but other chaperones termed DnaJ proteins by manipulating substrate selection and Hsp70 ATPase activity dictate whether this Hsp70-bound tau should be preserved, sequestered or destroyed. Therefore, we will test the hypothesis that regulation of tau triage by Hsp70 proteins is mediated through the Hsp70/DnaJ interface by: 1) determining whether chemical modulation of the DnaJ- binding domain on Hsp70 proteins regulates tau stability in vivo; 2) determining whether genetic modulation of the DnaJ-binding domain on Hsp73 regulates tau stability in vivo; and 3) determining whether modulating discreet DnaJ proteins directly can regulate tau processing in vivo. Successful completion of these studies will prove the relevance of the DnaJ/Hsp70 interface as a possible treatment for AD, PD, TBI and more than 15 other neurodegenerative diseases termed tauopathies.

描述（由申请人提供）： 微管相关蛋白tau的积累与阿尔茨海默病（AD）、帕金森病和创伤性脑损伤（TBI）中的神经元死亡相关。因此，tau是这些疾病中每一种的易处理的治疗靶标。蛋白质的伴侣蛋白家族，特别是热休克蛋白70家族，对tau蛋白的加工至关重要。事实上，Hsp 70家族的主要胞质变体Hsp 73与粒空泡变性体（GVD）强烈相关，粒空泡变性体是AD神经元中与自噬清除机制相关的主要tau相关病理实体。共定位研究还表明，Hsp 73与脑中积累的tau蛋白相关。然而，涉及Hsp 70家族与tau生物学的实际机制一直难以定义。热休克蛋白70既可以促进tau蛋白的清除，也可以在功能上保护tau蛋白的清除。我们已经发现，Hsp 70蛋白的作用是寻找，识别和保持tau蛋白，但其他分子伴侣称为DnaJ蛋白通过操纵底物选择和Hsp 70 ATP酶活性决定这种Hsp 70结合的tau蛋白是否应该被保留，隔离或破坏。因此，我们将通过以下方式检验Hsp 70蛋白对tau分类的调节是通过Hsp 70/DnaJ界面介导的假设：1）确定Hsp 70蛋白上DnaJ结合结构域的化学调节是否调节体内tau稳定性; 2）确定Hsp 73上DnaJ结合结构域的遗传调节是否调节体内tau稳定性;和3）确定直接调节离散DnaJ蛋白是否可以调节体内tau加工。这些研究的成功完成将证明DnaJ/Hsp 70界面作为AD、PD、TBI和超过15种其他称为tau蛋白病的神经退行性疾病的可能治疗的相关性。