TY - JOUR
T1 - Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain
AU - Cao, Yang
AU - Chtarbanova, Stanislava
AU - Petersen, Andrew J.
AU - Ganetzky, Barry
PY - 2013/5/7
Y1 - 2013/5/7
N2 - 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.
AB - 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.
KW - Neuronal cell death
KW - Neuroprotection
KW - Neurotoxic mechanism
UR - http://www.scopus.com/inward/record.url?scp=84877348381&partnerID=8YFLogxK
U2 - 10.1073/pnas.1306220110
DO - 10.1073/pnas.1306220110
M3 - Article
C2 - 23613578
AN - SCOPUS:84877348381
VL - 110
SP - E1752-E1760
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 19
ER -