Drosophila Toll-9 is induced by aging and neurodegeneration to modulate stress signaling and its deficiency exacerbates tau-mediated neurodegeneration

Yasufumi Sakakibara; Risa Yamashiro; Sachie Chikamatsu; Yu Hirota; Yoko Tsubokawa; Risa Nishijima; Kimi Takei; Michiko Sekiya; Koichi M Iijima

doi:10.1016/j.isci.2023.105968

Drosophila Toll-9 is induced by aging and neurodegeneration to modulate stress signaling and its deficiency exacerbates tau-mediated neurodegeneration

iScience. 2023 Jan 13;26(2):105968. doi: 10.1016/j.isci.2023.105968. eCollection 2023 Feb 17.

Authors

Yasufumi Sakakibara¹, Risa Yamashiro², Sachie Chikamatsu^{1

2}, Yu Hirota^{1

3}, Yoko Tsubokawa¹, Risa Nishijima¹, Kimi Takei¹, Michiko Sekiya^{1

2}, Koichi M Iijima^{1

2}

Affiliations

¹ Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
² Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
³ Reseach Fellow of Japan Society for the Promotion of Science, Tokyo, Japan.

Abstract

Drosophila Toll-9 is most closely related to mammalian Toll-like receptors; however, physiological functions of Toll-9 remain elusive. We examined the roles of Toll-9 in fly brains in aging and neurodegeneration. Toll-9 mRNA levels were increased in aged fly heads accompanied by activation of nuclear factor-kappa B (NF-kB) and stress-activated protein kinase (SAPK) signaling, and many of these changes were modulated by Toll-9 in glial cells. The loss of Toll-9 did not affect lifespan or brain integrity, whereas it exacerbated hydrogen peroxide-induced lethality. Toll-9 expression was also induced by nerve injury but did not affect acute stress response or glial engulfment activity, suggesting Toll-9 may modulate subsequent neurodegeneration. In a fly tauopathy model, Toll-9 deficiency enhanced neurodegeneration and disease-related tau phosphorylation with reduced SAPK activity, and blocking SAPK enhanced tau phosphorylation and neurodegeneration. In sum, Toll-9 is induced upon aging and nerve injury and affects neurodegeneration by modulating stress kinase signaling.

Keywords: Biological sciences; Molecular neuroscience; Neuroscience.