Mutation in pre-mRNA adenosine deaminase markedly attenuates neuronal tolerance to O2 deprivation in Drosophila melanogaster
Enbo Ma, … , Tian Xu, Gabriel G. Haddad
Enbo Ma, … , Tian Xu, Gabriel G. Haddad
Published March 15, 2001
Citation Information: J Clin Invest. 2001;107(6):685-693. https://doi.org/10.1172/JCI11625.
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Article

Mutation in pre-mRNA adenosine deaminase markedly attenuates neuronal tolerance to O2 deprivation in Drosophila melanogaster

Abstract

O2 deprivation can produce many devastating clinical conditions such as myocardial infarct and stroke. The molecular mechanisms underlying the inherent tissue susceptibility or tolerance to O2 lack are, however, not well defined. Since the fruit fly, Drosophila melanogaster, is extraordinarily tolerant to O2 deprivation, we have performed a genetic screen in the Drosophila to search for loss-of-function mutants that are sensitive to low O2. Here we report on the genetic and molecular characterization of one of the genes identified from this screen, named hypnos-2. This gene encodes a Drosophila pre-mRNA adenosine deaminase (dADAR) and is expressed almost exclusively in the adult central nervous system. Disruption of the dADAR gene results in totally unedited sodium (Para), calcium (Dmca1A), and chloride (DrosGluCl-α) channels, a very prolonged recovery from anoxic stupor, a vulnerability to heat shock and increased O2 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 O2 deprivation and for the prevention of premature neuronal degeneration.

Authors

Enbo Ma, Xiang-Qun Gu, Xiaohui Wu, Tian Xu, Gabriel G. Haddad

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Cloning of a Drosophila pre-mRNA adenosine deaminase (dADAR) (a) Schemat...
Cloning of a Drosophila pre-mRNA adenosine deaminase (dADAR) (a) Schematic representation of the organization of dADAR gene. The wild-type dADAR gene consists of ten exons and nine introns. In hypnos-2P, 434 bp of genomic DNA, marked by two arrowheads, have been deleted. (b) A domain map shows schematically a deduced dADAR protein that contains two double-stranded RNA-binding domains (dsRBDs; shaded boxes) and the deaminase domain with its putative Zn+-chelating residues (asterisks). (c) Alignment among Drosophila (D), rat (R; accession number S78526), and human (H; accession number X99383) ADAR proteins. Gaps are introduced for optimal alignment; identical residues are highlighted. The nuclear localization signal (NLS) is underlined and labeled at the end of the NH2 terminal. The two dsRBDs are underlined and labeled, and the three Zn+-chelating residues are bold and marked with asterisks. The deleted fragment in hypnos-2P mutation is marked by two flanking arrowheads. The identities between dADAR and rADAR and between dADAR and hADAR are 43% and 44%, respectively. The GenBank accession number for dADAR cDNA is AF343579.