Neuronal quality control and neuroprotection in tauopathies

树突简化和突触丢失是阿尔茨海默病痴呆的主要结构相关性 疾病（AD）和额颞叶痴呆（FTD）。微管相关蛋白tau的突变是一种 FTD的主要原因，并增加AD的风险。含Valosin蛋白（VCP）突变 也与家族性FTD有关。在之前的项目期间，我们发现树突状钙 稳态失调、线粒体自噬失调和蛋白质磷酸化改变有助于树突状细胞凋亡。 在几种神经变性模型中的收缩。我们还发现了VCP和 神经保护性激酶PTEN诱导的激酶1（PINK1）。VCP是一种多功能蛋白质， 蛋白质降解、囊泡运输和高尔基体重塑，这些功能由不同的 VCP辅因子。基于初步数据，我们假设PINK1与VCP相互作用以阻止tau蛋白的表达。 介导的树突收缩。我们将利用原代啮齿动物皮层神经元和人类iPSC衍生的神经元。 神经元研究质量控制机制，有助于对tau介导的神经保护 树枝状乔木和刺的退化。我们还将评估上调神经保护作用的潜力。 PINK1信号在体外和体内。这些研究的完成将揭示蛋白质如何参与不同的 神经变性疾病一起起作用以防止tau介导的神经变性。

Dendritic simplification and synaptic loss represent major structural correlates of dementia in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Mutations in the microtubule-associated protein tau are a major cause of FTD and increase the risk of developing AD. Mutations in valosin-containing protein (VCP) have also been linked to familial FTD. In the prior project period, we discovered that dendritic calcium dyshomeostasis, dysregulated mitophagy and altered protein phosphorylation contribute to dendritic shrinkage in several models of neurodegeneration. We also discovered a novel interaction between VCP and the neuroprotective kinase PTEN-induced kinase 1 (PINK1). VCP is a multifunctional protein implicated in protein degradation, vesicular transport and Golgi remodeling, and these functions are mediated by distinct VCP cofactors. Based on preliminary data, we hypothesize that PINK1 interacts with VCP to prevent tau- mediated dendritic shrinkage. We will utilize primary rodent cortical neurons and human iPSC-derived neurons to study quality control mechanisms that contribute to neuroprotection against tau-mediated degeneration of dendritic arbors and spines. We will also assess the neuroprotective potential of upregulating PINK1 signaling in vitro and in vivo. Completion of these studies will reveal how proteins implicated in different neurodegenerative diseases function together to protect against tau-mediated neurodegeneration.