A Drosophila model of diabetic neuropathy reveals a role of proteasome activity in the glia

• Published in: iScience Vol. 26; no. 6; p. 106997
• Main Authors: Suzuki, Mari, Kuromi, Hiroshi, Shindo, Mayumi, Sakata, Nozomi, Niimi, Naoko, Fukui, Koji, Saitoe, Minoru, Sango, Kazunori
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.06.2023; Elsevier
• Subjects: Cell biology; Cellular physiology; Pathophysiology; Pathophysiology; Cell biology; Cellular physiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106997

Diabetic peripheral neuropathy (DPN) is the most common chronic, progressive complication of diabetes mellitus. The main symptom is sensory loss; the molecular mechanisms are not fully understood. We found that Drosophila fed a high-sugar diet, which induces diabetes-like phenotypes, exhibit impairment of noxious heat avoidance. The impairment of heat avoidance was associated with shrinkage of the leg neurons expressing the Drosophila transient receptor potential channel Painless. Using a candidate genetic screening approach, we identified proteasome modulator 9 as one of the modulators of impairment of heat avoidance. We further showed that proteasome inhibition in the glia reversed the impairment of noxious heat avoidance, and heat-shock proteins and endolysosomal trafficking in the glia mediated the effect of proteasome inhibition. Our results establish Drosophila as a useful system for exploring molecular mechanisms of diet-induced peripheral neuropathy and propose that the glial proteasome is one of the candidate therapeutic targets for DPN. [Display omitted] •High dietary sugar leads to impairment of noxious heat avoidance in Drosophila•Leg sensory neurons became atrophic on high-sugar feeding•Proteasome inhibition in glia suppresses impairment of noxious heat response•HSPs and endolysosomal trafficking mediate the effects of proteasome inhibition Pathophysiology; Cellular physiology; Cell biology