A Drosophila model of diabetic neuropathy reveals a role of proteasome activity in the glia
Mari Suzuki,
Hiroshi Kuromi,
Mayumi Shindo,
Nozomi Sakata,
Naoko Niimi,
Koji Fukui,
Minoru Saitoe,
Kazunori Sango
Affiliations
Mari Suzuki
Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan; Corresponding author
Hiroshi Kuromi
Learning and Memory Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan
Mayumi Shindo
Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan
Nozomi Sakata
Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan; Department of Bioscience and Engineering, Shibaura Institute of Technology, Saitama 337-8570, Japan
Naoko Niimi
Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan
Koji Fukui
Department of Bioscience and Engineering, Shibaura Institute of Technology, Saitama 337-8570, Japan
Minoru Saitoe
Learning and Memory Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan
Kazunori Sango
Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan; Corresponding author
Summary: 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.
