Mutation in pre-mRNA adenosine deaminase markedly attenuates neuronal tolerance to O-2 deprivation in Drosophila melanogaster

O-2 deprivation can produce many devastating clinical conditions such as my ocardial infarct and stroke. The molecular mechanisms underlying the inhere nt tissue susceptibility or tolerance to O-2 lack are, however, not well de fined. Since the fruit fly, Drosophila melanogaster, is extraordinarily tol erant to O-2 deprivation, we have performed a genetic screen in the Drosoph ila to search for loss-of-function mutants that are sensitive to low O-2. H ere we report on the genetic and molecular characterization of one of the g enes identified from this screen, named hypnos-2. This gene encodes a Droso phila pre-mRNA adenosine deaminase (dADAR) and is expressed almost exclusiv ely in the adult central nervous system. Disruption of the dADAR gene resul ts in totally unedited sodium (Para), calcium (Dmca1A), and chloride (DrosG luCl-alpha) channels, a very prolonged recovery from anoxic stupor, a vulne rability to heat shock and increased O-2 demands, and neuronal degeneration in aged flies. These data clearly demonstrate that, through the editing of ion channels as targets, dADAR, for which there are mammalian homologues, is essential for adaptation to altered environmental stresses such as O-2 d eprivation and for the prevention of premature neuronal degeneration.