Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration

增强MASK/ANKHD1活性以保护Tau诱导的神经变性 摘要 遗传性和散发性神经退行性变的共同病理生理特征 阿尔茨海默病等疾病是胞浆内堆积的包裹体，包含 容易聚集的蛋白质，如Tau。越来越多的证据也表明，这种异常 神经退行性疾病患者神经元和神经胶质细胞中的包涵体可以扩散到 神经系统内的细胞边界以类似于普里恩的方式。因此，加强 清除有毒蛋白质聚集体具有巨大的治疗潜力 神经退行性变。我们发现上调的MASK-A保守的Ankyrin重复和KH 结构域蛋白(人类同源物称为ANKHD1)--在果蝇神经系统疾病模型中 显著抑制人突变型Tau、FUS和TDP-43诱导的变性。我们是下一个 获得生化、细胞和遗传学证据，证明口罩既是必要的，也是充分的 促进泛素化蛋白质的清除，它通过促进溶酶体来做到这一点 酸化和增强自噬的通量。我们还发现，哺乳动物 MASK的同源物ANKHD1也可能促进自噬通量。这些结果使我们得出了 假说增强MASK/ANKHD1活性促进自噬/溶酶体 途径，在清除有毒蛋白质聚集体方面具有整体有益的效果，以及 因此可能具有进一步开发和测试作为治疗策略的潜力 阿尔茨海默氏症。这项资助旨在测试1)MASK介导的溶酶体促进 功能抑制人牛磺酸诱导的果蝇神经变性；以及2)是否 ANKHD1共表达抑制人突变引起的神经元特异性变性 小鼠模型中的tau蛋白。

Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration Abstract A common pathophysiological feature of both inherited and sporadic neurodegenerative diseases such as Alzheimer’s disease is the cytoplasmic accumulation of inclusions containing aggregate-prone proteins such as Tau. Mounting evidence also suggested that such abnormal inclusions in neurons and glial cells of neurodegenerative disease patients can spread across cellular boundaries within the nervous system in a prion-like manner. Therefore, enhancing the clearance of the toxic protein aggregates holds tremendous therapeutic potential for treating neurodegeneration. We found that upregulating Mask – a conserved Ankyrin repeats and KH domain protein (the human homologue is called ANKHD1) – in fly neurological disease model markedly suppresses human mutant Tau-, FUS- and TDP-43-induced degeneration. We next obtained biochemical, cellular, and genetic evidence that Mask is both necessary and sufficient to promote clearance of ubiquitinated proteins, and it does so by promoting lysosomal acidification and enhancing the flux of autophagy. We also found that the mammalian homologue of Mask, ANKHD1, may also promote autophagic flux. These results led us to hypothesize that enhancing Mask/ANKHD1 activity promotes the autophagy/lysosomal pathway, which has an overall beneficial effect in removing of toxic protein aggregates, and therefore may have the potential to be further developed and tested as a therapeutic strategy for Alzheimer’s disease. This grant aims to test 1) whether Mask-mediated promotion of lysosomal function suppresses neurodegeneration induced by human Tau in flies; and 2) whether ANKHD1 co-expression suppresses neuron-specific degeneration induced by human mutated Tau in mouse models.