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

增强Mask/ANKHD 1活性以防止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 阿尔茨海默氏病等疾病是细胞质中含有 聚集倾向蛋白质，如Tau。越来越多的证据也表明， 神经退行性疾病患者的神经元和神经胶质细胞中的内含物可以扩散到 以朊病毒样的方式破坏神经系统内的细胞边界。因此，加强 毒性蛋白聚集体的清除具有巨大的治疗潜力 神经变性我们发现上调Mask -保守的锚蛋白重复序列和KH 结构域蛋白（人类同源物称为ANKHD 1）-在苍蝇神经疾病模型中 显著抑制人突变型Tau-、FUS-和TDP-43诱导的变性。我们接下来 获得了生化，细胞和遗传证据，Mask是必要的，也是足够的 促进泛素化蛋白的清除，并通过促进溶酶体 酸化和增强自噬的通量。我们还发现哺乳动物 Mask同源物ANKHD 1也可促进自噬通量。这些结果使我们 假设增强Mask/ANKHD 1活性促进自噬/溶酶体 途径，其在去除有毒蛋白质聚集体方面具有总体有益效果，以及 因此，可能有潜力作为治疗策略进行进一步开发和测试， 老年痴呆症这项资助旨在测试1）Mask介导的溶酶体促进是否 功能抑制果蝇中由人Tau诱导的神经变性;以及2）是否 ANKHD 1共表达抑制人突变型ANKHD诱导的神经元特异性变性 小鼠模型中的Tau。

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.