title: ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila.
abstract: To investigate the mechanistic basis for central nervous system (CNS) neurodegeneration in the disease ataxia-telangiectasia (A-T), we analyzed flies mutant for the causative gene A-T mutated (ATM). ATM encodes a protein kinase that functions to monitor the genomic integrity of cells and control cell cycle, DNA repair, and apoptosis programs. Mutation of the C-terminal amino acid in Drosophila ATM inhibited the kinase activity and caused neuron and glial cell death in the adult brain and a reduction in mobility and longevity. These data indicate that reduced ATM kinase activity is sufficient to cause neurodegeneration in A-T. ATM kinase mutant flies also had elevated expression of innate immune response genes in glial cells. ATM knockdown in glial cells, but not neurons, was sufficient to cause neuron and glial cell death, a reduction in mobility and longevity, and elevated expression of innate immune response genes in glial cells, indicating that a non-cell-autonomous mechanism contributes to neurodegeneration in A-T. Taken together, these data suggest that early-onset CNS neurodegeneration in A-T is similar to late-onset CNS neurodegeneration in diseases such as Alzheimer's in which uncontrolled inflammatory response mediated by glial cells drives neurodegeneration.
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Petersen
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Rimkus
authors.forename: David A
authors.initials: DA
authors.lastname: Wassarman
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D055785:Gene Knockdown Techniques; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D008136:Longevity; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009457:Neuroglia / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013696:Temperature; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C514947:Tefu protein, Drosophila