The Innate Immune Response Transcription Factor Relish Is Necessary for Neurodegeneration in a Drosophila Model of Ataxia-Telangiectasia

摘要

Neurodegeneration is a hallmark of the human disease ataxia-telangiectasia (A-T) that is caused by mutation of the A-T mutated () gene. We have analyzed Drosophila melanogaster mutants to determine the molecular mechanisms underlying neurodegeneration in A-T. Previously, we found that mutants upregulate the expression of innate immune response (IIR) genes and undergo neurodegeneration in the central nervous system. Here, we present evidence that activation of the IIR is a cause of neurodegeneration in mutants. Three lines of evidence indicate that mutations cause neurodegeneration by activating the Nuclear Factor-κB (NF-κB) transcription factor Relish, a key regulator of the Immune deficiency (Imd) IIR signaling pathway. First, the level of upregulation of IIR genes, including Relish target genes, was directly correlated with the level of neurodegeneration in mutants. Second, mutations inhibited upregulation of IIR genes and neurodegeneration in mutants. Third, overexpression of constitutively active Relish in glial cells activated the IIR and caused neurodegeneration. In contrast, we found that and mutations did not affect neurodegeneration in mutants. encodes an activator of Relish in the response to gram-negative bacteria, and encodes an immune responsive NF-κB transcription factor in the Toll signaling pathway. These data indicate that the signal that causes neurodegeneration in mutants activates a specific NF-κB protein and does so through an unknown activator. In summary, these findings suggest that neurodegeneration in human A-T is caused by activation of a specific NF-κB protein in glial cells.