Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-05, Vol.110 (19), p.E1752-E1760
• Main Authors: Cao, Yang, Chtarbanova, Stanislava, Petersen, Andrew J, Ganetzky, Barry
• Format: Article
• Language: English
• Subjects: Aging; Animals; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Apoptosis; Bacterial Infections - genetics; Bacterial Infections - immunology; Biological Sciences; Brain; Brain - immunology; Brain - microbiology; Brain - pathology; Cell Death; Drosophila melanogaster - genetics; Drosophila melanogaster - immunology; Drosophila melanogaster - microbiology; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Genes; Genotype; Immune system; Immunity, Innate; Insects; Mutation; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - immunology; Neurodegenerative Diseases - pathology; Neurons - pathology; Phenotype; PNAS Plus; Repressor Proteins - genetics; Transcription Factors - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1306220110

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.