title: Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain.
abstract: A growing body of evidence in humans implicates chronic activation of the innate immune response in the brain as a major cause of neuropathology in various neurodegenerative conditions, although the mechanisms remain unclear. In an unbiased genetic screen for mutants exhibiting neurodegeneration in Drosophila, we have recovered a mutation of dnr1 (defense repressor 1), a negative regulator of the Imd (immune deficiency) innate immune-response pathway. dnr1 mutants exhibit shortened lifespan and progressive, age-dependent neuropathology associated with activation of the Imd pathway and elevated expression of AMP (antimicrobial peptide) genes. To test the hypothesis that overactivation of innate immune-response pathways in the brain is responsible for neurodegeneration, we demonstrated that direct bacterial infection in the brain of wild-type flies also triggers neurodegeneration. In both cases, neurodegeneration is dependent on the NF-κB transcription factor, Relish. Moreover, we found that neural overexpression of individual AMP genes is sufficient to cause neurodegeneration. These results provide a mechanistic link between innate immune responses and neurodegeneration and may have important implications for the role of neuroinflammation in human neurodegenerative diseases as well.
authors.affiliation: Laboratory of Genetics, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Stanislava
authors.initials: S
authors.lastname: Chtarbanova
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Petersen
authors.forename: Barry
authors.initials: B
authors.lastname: Ganetzky
mesh_terms: D000375:Aging; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D016923:Cell Death; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D005838:Genotype; D007113:Immunity, Innate; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; C540765:Dnr1 protein, Drosophila; D029721:Drosophila Proteins; C101626:Rel protein, Drosophila; D012097:Repressor Proteins; D014157:Transcription Factors
keywords: neuronal cell death; neuroprotection; neurotoxic mechanism