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

作者：Cao Yang; Chtarbanova Stanislava; Petersen Andrew J; Ganetzky Barry^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(19): E1752-E1760.

DOI：10.1073/pnas.1306220110

• neuroprotection
• neuronal cell death
• neurotoxic mechanism

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-kappa B 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.

• 出版日期2013-5-7