ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration inDrosophila
- 21 February 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (11), E656-64
- https://doi.org/10.1073/pnas.1110470109
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.Keywords
This publication has 68 references indexed in Scilit:
- Toll-like receptors are key players in neurodegenerationInternational Immunopharmacology, 2011
- Nuclear initiated NF-κB signaling: NEMO and ATM take center stageCell Research, 2010
- Multiple roles of ATM in monitoring and maintaining DNA integrityFEBS Letters, 2010
- Development‐based compartmentalization of the Drosophila central brainJournal of Comparative Neurology, 2010
- The cleaved-Caspase-3 antibody is a marker of Caspase-9-like DRONC activity in DrosophilaCell Death & Differentiation, 2009
- Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyondThe Journal of cell biology, 2009
- Emerging common themes in regulation of PIKKs and PI3KsThe EMBO Journal, 2009
- Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutantsNature Reviews Genetics, 2009
- GATA factors participate in tissue-specific immune responses in Drosophila larvaeProceedings of the National Academy of Sciences of the United States of America, 2006
- DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociationNature, 2003