Suzuki Mari, Kuromi Hiroshi, Shindo Mayumi, Sakata Nozomi, Niimi Naoko, Fukui Koji, Saitoe Minoru, Sango Kazunori
Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan.
Learning and Memory Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan.
iScience. 2023 May 29;26(6):106997. doi: 10.1016/j.isci.2023.106997. eCollection 2023 Jun 16.
Diabetic peripheral neuropathy (DPN) is the most common chronic, progressive complication of . The main symptom is sensory loss; the molecular mechanisms are not fully understood. We found that 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 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 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.
糖尿病性周围神经病变（DPN）是糖尿病最常见的慢性、进行性并发症。主要症状是感觉丧失；其分子机制尚未完全明确。我们发现，喂食高糖饮食（可诱发类似糖尿病的表型）的小鼠表现出对伤害性热刺激回避能力受损。热刺激回避能力受损与表达瞬时受体电位通道Painless的腿部神经元萎缩有关。通过候选基因筛选方法，我们确定蛋白酶体调节剂9是热刺激回避能力受损的调节因子之一。我们进一步表明，神经胶质细胞中的蛋白酶体抑制可逆转伤害性热刺激回避能力的受损，并且神经胶质细胞中的热休克蛋白和内体溶酶体运输介导了蛋白酶体抑制的作用。我们的结果确立了小鼠作为探索饮食诱导的周围神经病变分子机制的有用模型，并提出神经胶质蛋白酶体是DPN的候选治疗靶点之一。
