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

增强 Mask/ANKHD1 活性以预防 Tau 诱导的神经变性

基本信息

批准号：
10288299
负责人：
Chunlai Wu
金额：
$ 40.43万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288299
关键词：
Alternative Splicing Alzheimer&apos s Disease Ankyrin Repeat Autophagocytosis Biochemical Brain Data Disease Disease model Drosophila genus Genetic Glutamates Grant Homologous Gene Human Inherited KH Domain Lead Lysosomes Mammalian Cell Mammals Masks Mediating Modeling Molecular Mus Mutate Mutation Names Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuroglia Neurons Pathogenesis Pathologic Pathway interactions Patients Protein Isoforms Proteins Proton Pump RNA Splicing Role Sequence Homology Tauopathies Tertiary Protein Structure Testing Therapeutic Toxic effect Transgenes Up-Regulation fly gain of function mouse model mutant nervous system disorder novel strategies overexpression photoreceptor degeneration prion-like protective effect protein TDP-43 protein aggregation proteostasis tau Proteins tau aggregation tau mutation vacuolar H+-ATPase

项目摘要

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.

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，这种不正常的情况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，可能有潜力进一步开发和测试作为一种治疗策略，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。