DnaJB6 as a novel regulator of tau

摘要 阿尔茨海默病(AD)是一种进行性神经退行性疾病，其特征是由 病理性牛磺酸的沉积。因此，识别和定位tau的有效调控因子在开发 有效的治疗策略。我的令人兴奋的初步数据显示，Dna JB6的过度表达降低了tau 在HEK293T细胞中的表达水平超过50%，同时，Dna JB6的敲除导致 陶先生。这表明Dna JB6可能调节tau水平，然而，这种关系的性质还没有。 被调查过了。在这个提案中，我将测试Dna JB6可以通过以下方式防止tau积累的假设 直接机制和间接机制。在目标1中，我将通过评估蛋白质-蛋白质相互作用动力学来测试这一点 用硫代黄素T荧光和表面重组法检测DNAJB6和tau之间的相互作用 等离子激元共振。将使用有针对性的蛋白质组学方法来确定直接和最近的连接 在初级神经元中，DNAJB6和tau之间。在目标2中，我们将使用PS19和非转基因小鼠来评估 Dna JB6在大脑中过表达导致的相关行为和分子变化。 这些研究的成功完成将提供有关DNAJB6生物学、直接和 Dna JB6对tau的间接作用，以及Dna JB6的调节如何影响大鼠的行为和分子变化 神经节律的大脑。

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by neuronal loss driven by deposits of pathological tau. Therefore, identifying and targeting potent regulators of tau is crucial in developing effective therapeutic strategies. My exciting preliminary data show DnaJB6 overexpression decreases tau levels in HEK293T cells more than 50%, and in parallel, knockdown of DnaJB6 results in a 2-fold increase of tau. This suggests that DnaJB6 may regulate tau levels, however, the nature of this relationship has not yet been investigated. In this proposal, I will test the hypothesis that DnaJB6 can prevent tau accumulation through direct and indirect mechanisms. In Aim 1, I will test this through assessing protein-protein interaction dynamics between DnaJB6 and tau with recombinant in vitro assays, including Thioflavin T fluorescence and Surface Plasmon Resonance. A targeted proteomic approach will be used to identify direct and proximal connections between DnaJB6 and tau in primary neurons. In Aim 2, we will use PS19 and non-transgenic mice to assess the associated behavioral and molecular changes that result from DnaJB6 overexpression in the brain. Successful completion of these studies will provide crucial information regarding DnaJB6 biology, direct and indirect effects of DnaJB6 on tau, and how regulation of DnaJB6 affects behavioral and molecular changes in the tauopathic brain.