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

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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.