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因素 阿尔茨海默病(AD)和额颞痴呆(FTD)。微管相关蛋白tau的突变是一种 FTD的主要原因，增加了发展为AD的风险。含有Valosin的蛋白(VCP)的突变 也与家族性FTD有关。在之前的项目期间，我们发现树枝状钙 动态平衡失调、吞噬核分裂异常和蛋白磷酸化改变导致树突状细胞 几种神经退行性变模型中的萎缩。我们还发现了VCP和VCP之间的一种新的相互作用 神经保护性激酶PTEN诱导的激酶1(PINK1)。VCP是一种多功能蛋白，与 蛋白质降解、囊泡运输和高尔基体重塑，这些功能是由不同的 VCP辅助因子。根据初步数据，我们假设PINK1与VCP相互作用，以防止tau- 介导性枝晶收缩。我们将利用原代啮齿动物皮质神经元和人类IPSC来源的 神经元将研究有助于神经保护免受tau介导的质量控制机制 树枝和刺的退化。我们还将评估上调的神经保护潜力。 体外和体内的PINK1信号转导。这些研究的完成将揭示蛋白质如何与不同的 神经退行性疾病共同发挥作用，防止tau介导的神经退行性变。

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.