EDTP/MTMR14: A novel target for improved survivorship to prolonged anoxia and cellular protein aggregates

Drosophila egg-derived tyrosine phosphatase (EDTP), a lipid phosphatase that removes 3-position phosphate at the inositol ring, has dual functions in oogenesis and muscle performance in adults. A mammalian homologous gene MTMR14, which encodes the myotubularin-related protein 14, negatively regulates autophagy. Mutation of EDTP/MTMR14, however, causes at least three deleterious consequences: (1) the lethality in early embryogenesis in Drosophila; (2) a "jumpy" phenotype with apparently impaired motor functions; and (3) an association with a rare genetic disorder called centronuclear myopathy. The potential benefit of EDTP/MTMR14 downregulation is likely masked by the lethality or severe muscle defects due to ubiquitous loss of this gene. Here we show that flies carrying a heterozygous EDTP mutation had increased survivorship to prolonged anoxia; tissue-specific downregulation of EDTP in non-muscle tissues, particularly motoneurons, extended lifespan and improved survivorship to beta-amyloid peptides (Aβ42) and polyglutamine protein aggregates. These data highlight the significance of selective downregulation of EDTP in non-muscles for beneficial consequences. MTMR14 expression was evident in the hippocampus and cortex in C57BL/6 J and APP/PS1 mice. Compared with C57BL/6 J mice, APP/PS1 mice had reduced MTMR14 in the cortex. Hippocampal expression of MTMR14 was increased and plateaued at 9-17 months compared with 2-6 months in C57BL/6 J mice. Additionally, MTMR14 was inducible by Aβ42 in the rat primarily hippocampal neurons and mouse Neuro2a neuroblasts. We demonstrate a novel approach of tissue-specific downregulation of the disease-associated gene EDTP/MTMR14 for extended lifespan and improved survivorship to cellular protein aggregates. This approach could be extended from insects to mammals.