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

描述(由申请人提供)： 微管相关蛋白tau的积聚与阿尔茨海默病(AD)、帕金森病和创伤性脑损伤(TBI)中的神经元死亡有关。因此，tau是这些疾病的有效治疗靶点。伴侣蛋白家族，特别是热休克蛋白70家族，对tau的加工至关重要。事实上，Hsp70家族的主要胞浆变异体Hsp73与颗粒泡变性小体(GVD)密切相关，GVD是AD神经元中与tau相关的主要病理实体，与自噬清除机制有关。共定位研究还表明，Hsp73与大脑中积累的tau有关。然而，Hsp70家族与tau生物学相关的实际机制一直难以定义。HSP70蛋白既可以促进tau的清除，也可以在功能上保护tau。最近，我们已经开始阐明这种二分法的原因。我们已经发现，Hsp70蛋白起到寻找、识别和结合tau的作用，但其他被称为DNAJ蛋白的伴侣通过操纵底物选择和Hsp70 ATPase活性来决定这种与Hsp70结合的tau是应该被保存、隔离还是销毁。因此，我们将检验这一假设，即Hsp70蛋白对tau分流的调节是通过Hsp70/Dna J界面介导的：1)确定Hsp70蛋白上Dna结合结构域的化学调节是否调节体内tau的稳定性；2)确定Hsp73上Dna J结合结构域的遗传调节是否调节体内tau的稳定性；以及3)确定直接调节离散的Dna J蛋白是否可以调节体内tau的加工。这些研究的成功完成将证明DNAJ/Hsp70接口作为一种可能的治疗AD、PD、TBI和其他15种称为tauopathy的其他神经退行性疾病的方法具有相关性。

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.