Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of Diabetes Mellitus (DM). DPN is characterized by progressive, nerve length-dependent loss of peripheral nerve fibers, leading to decreased sensation, spontaneous pain, and eventually complete loss of sensation. Despite worldwide intensive research, the pathogenesis of DPN remains largely unknown, and no effective therapies for DPN have been established. Drosophila melanogaster is a suitable animal model for genetic analyses and is also useful for the study of DM because the organs and molecular regulators of energy metabolism in Drosophila are mostly analogous to those in humans. Like humans, adult flies fed a high-sugar diet (HSD) develop type 2 DM-like phenotypes, such as hyperglycemia and insulin resistance. Drosophila has also been utilized to elucidate the mechanisms of nociception under physiological and pathological conditions; however, whether dietary-induced diabetic conditions induce sensory disturbances in adult flies remains unknown.
HSD-fed Drosophila exhibited diabetes-like phenotypes and impairment of noxious heat avoidance. The heat avoidance impairment was associated with atrophy of the leg neurons expressing the Drosophila transient receptor potential channel Painless. A candidate genetic screening approach resulted in the identification of proteasome 26S subunit, non-ATPase 9 (PSMD9) as one of the modulators of heat avoidance impairment. Further analyses revealed that glia-specific PSMD knockdown or proteasome inhibition reversed the impaired heat avoidance, and that heat-shock proteins and endolysosomal trafficking in the glia mediated the protective effect of proteasome inhibition (Fig.1). These findings establish HSD-fed Drosophila as a useful model for exploring molecular mechanisms of DPN and suggest the glial proteasome as one of the potential therapeutic targets for DPN.
![[Fig.1] Proteasome activity in the glia as one of the potential therapeutic targets for diabetic peripheral neuropathy.](/english/topics/2023/fig0616e.jpg)
