PINK1 protects neurons against mutant Tau pathology

项目摘要/摘要 摘要：蛋白质平衡受到严格的调控，需要高效的蛋白质合成、运输和 退化。蛋白质堆积、定位错误和树突简化是病理性的。 神经退行性疾病的特征，包括阿尔茨海默病(AD)额颞部 痴呆症(FTD)、帕金森氏病(PD)和帕金森氏病伴痴呆(PDD)。尽管有不同的 在遗传和环境病因学上，这些疾病有一个共同特征，即Tau异常 职能、本地化或更替。Tau突变A152T与AD、FTD和 PDD。Tau-A152T增加Tau磷酸化，减少微管延伸，并导致 神经元死亡。PTEN诱导蛋白1(PINK1)的表达具有广泛的神经保护作用 以遗传和毒素为基础的神经退化模型。我们小组之前的研究表明， PINK1亚细胞池在调节线粒体分裂-融合中发挥着不同的作用， 有丝分裂、钙稳态和树突状形态发生。另外，我们发现， 胞质PINK1足以维持树突长度，并与含有Valosin的结合 蛋白(VCP/p97)，一种重要的II型AAA蛋白，参与蛋白稳态通路和 底物的降解。我的初步数据显示，增加PINK1的表达可以保护 神经元对抗突变型Tau介导的树突状简化并促进突变型Tau 退化。鉴于这些数据，我假设PINK1阻止突变的Tau(Tau-A152T) 通过PINK1与VCP的相互作用，促进突变的Tau降解。 利用生物化学、分子生物学、成像和细胞培养技术的组合，我 将检验PINK1表达升高将逆转突变的Tau病理的假设， 特别是树突状细胞萎缩、磷酸化和定位错误(目标1)，并测试是否 PINK1通过VCP促进突变体Tau的降解(目的2)。在完成这些目标后，我将 已经确定了PINK1具有神经保护作用的新途径，它不仅具有高度的 对规划PD和PDD靶向治疗的影响，但也可能在以下方面有广泛的应用 AD、FTD和其他tauopathy。

Project Summary/Abstract Abstract: Proteostasis is tightly regulated, requiring efficient protein synthesis, trafficking, and degradation. Protein accumulation, mislocalization, and dendritic simplification are pathological features of neurodegenerative diseases, including Alzheimer’s disease (AD) Frontotemporal Dementia (FTD), Parkinson’s disease (PD) and PD with dementia (PDD). Despite variations in genetic and environmental etiology, these diseases share a common feature of aberrant Tau function, localization, or turnover. The Tau mutation A152T has been linked to AD, FTD, and PDD. Tau-A152T increases Tau phosphorylation, reduces microtubule extension, and causes neuronal death. PTEN-inducible kinase 1 (PINK1) expression is neuroprotective in a wide range of genetic and toxin-based models of neurodegeneration. Prior studies from our group show that subcellular pools of PINK1 play divergent roles in regulating mitochondrial fission-fusion, mitophagy, calcium homeostasis and dendritic morphogenesis. Additionally, we found that cytosolic PINK1 is sufficient for maintaining dendrite length and binds with Valosin-containing Protein (VCP/p97), an essential type II AAA+ protein involved in proteostasis pathways and degradation of substrates. My preliminary data reveal that increased PINK1 expression protects neurons against mutant Tau-mediated dendritic simplification and promotes mutant Tau degradation. Given these data, I hypothesize that PINK1 prevents mutant Tau (Tau-A152T) pathology and promotes mutant Tau degradation through PINK1 interaction with VCP. Using a combination of biochemistry, molecular biology, imaging and cell culture techniques, I will test the hypothesis that elevated PINK1 expression will reverse mutant Tau pathology, specifically dendritic atrophy, phosphorylation, and mislocalization (Aim 1), and test whether PINK1 promotes mutant Tau degradation via VCP (Aim 2). Upon completion of these aims, I will have identified novel pathways in which PINK1 is neuroprotective, which will not only have high impact for planning PD- and PDD-targeted therapies, but may also have broad application for AD, FTD, and other tauopathies.