A Drosophila ortholog of Toll‐like receptors modulates c‐Jun N‐terminal kinase signaling and protects against tau‐mediated neurodegeneration independent of innate immune response

Abstract

AbstractBackgroundInnate immunity is dysregulated in aging and neurodegenerative diseases, and Toll‐like receptors (TLRs) play a central role in innate immune response. Nine Toll family receptors (Toll‐1 to Toll‐9) exist in Drosophila, and Toll‐9 is structurally most closely related to mammalian TLRs such as TLR1, 2, 6, 10. However, physiological roles of Toll‐9 in innate immunity and neurodegeneration are largely unknown. In this study, we examined roles of Toll‐9 in fly brains under neurodegenerative conditions.MethodWe systematically investigated potential roles of Toll‐9 in the maintenance of the brain integrity under neurodegenerative conditions, using Drosophila models of acute axon injury and human tau‐mediated neurodegeneration.ResultExpression level of Toll‐9 was very low in brains under normal condition but was dramatically increased upon acute nerve injury, suggesting a potential role of Toll‐9 in neurodegeneration. Innate immune response including induction of antimicrobial peptides and glial phagocytic activity of degenerating neurons were activated by nerve injury in fly brains, though Toll‐9 knockout did not affect these responses. Interestingly, however, Toll‐9 knockout significantly impaired activation of stress signaling cascades including c‐Jun N‐terminal kinase pathway. To ask whether Toll‐9 modify severity of neurodegeneration, we employed a fly model of tauopathy and found that Toll‐9 knockdown significantly exacerbated axon degeneration accompanied by pathological tau phosphorylation.ConclusionThese results demonstrate that Drosophila Toll‐9 confers neuroprotective effects through activation of stress kinase signaling independent of induction of innate immune genes, which may provide insights into the pathogenesis of neurodegenerative diseases.