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

Yang Cao, Stanislava Chtarbanova, Andrew J. Petersen, Barry Ganetzky

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

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 immuneresponse 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.

Original languageEnglish
Pages (from-to)E1752-E1760
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number19
DOIs
StatePublished - May 7 2013

Keywords

  • Neuronal cell death
  • Neuroprotection
  • Neurotoxic mechanism

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