Downregulation of EDTP in glial cells suppresses polyglutamine protein aggregates and extends lifespan in Drosophila melanogaster.

Drosophila egg-derived tyrosine phosphatase (EDTP) is a lipid phosphatase essential for oogenesis and muscle function. Loss-of-EDTP is lethal at early developmental stages. Hypomorphic mutation of EDTP causes impaired muscle performance and shortened lifespan. Mutation of MTMR14, a mammalian homolog to EDTP, is associated with muscle fatigue in rodents and a rare genetic disease called centronuclear myopathy in humans. Despite the deleterious consequences, downregulation of MTMR14 promotes autophagy. It is proposed that selective downregulation of EDTP/MTMR14 in non-muscle tissues improves the survivorship to cellular wastes and extends lifespan. Here, we show that downregulation of EDTP in glial cells suppressed the expression of polyglutamine (polyQ) protein aggregates and improved survival. Downregulation of EDTP in glial cells also extended lifespan. These effects were not observed by targeting pan-neurons in the nervous system, suggesting the significance of tissue-specificity. Additionally, flies carrying an EDTP mutant had increased survival to prolonged anoxia and altered dynamics of polyQ expression. These data supported the proposal that selective downregulation of EDTP in non-muscle tissues improved survivorship to cellular protein aggregates and extended lifespan. Our findings suggest that EDTP/MTMR14 could be a novel molecular target for the treatment of neurodegeneration.

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