Abstract
Background
Diabetic neuropathy (DN) is a prevalent and painful complication of diabetes; however, the mechanisms underlying its pathogenesis remain unclear, and effective clinical treatments are lacking. This study aims to explore the role of peroxisomes in Schwann cells in DN.
Methods
The abundance of peroxisomes in the sciatic nerves of mice or Schwann cells was analyzed using laser confocal super-resolution imaging and western blotting. The RFP-GFP-SKL (Ser-Lys-Leu) probe was utilized to assess pexophagy (peroxisomes autophagy) levels. To evaluate the palmitoylation of PEX11B, the acyl-resin assisted capture (acyl-RAC) assay and the Acyl-Biotin Exchange (ABE) assay were employed. Additionally, MR (Mendelian randomization) analysis was conducted to investigate the potential causal relationship between DN and MS (Multiple sclerosis).
Results
There was a decrease in peroxisomal abundance in the sciatic nerves of diabetic mice, and palmitic acid (PA) induced a reduction in peroxisomal abundance by inhibiting peroxisomal biogenesis in Schwann cells. Mechanistically, PA induced the palmitoylation of PEX11B at C25 site, disrupting its self-interaction and impeding peroxisome elongation. Fenofibrate, a PPARα agonist, effectively rescued peroxisomal dysfunction caused by PA and restored the peroxisomal abundance in diabetic mice. Lastly, MR analysis indicates a notable causal influence of DN on MS, with its onset and progression intricately linked to peroxisomal dysfunction.
Conclusions
Targeting the peroxisomal biogenesis pathway may be an effective strategy for preventing and treating DN, underscoring the importance of addressing MS risk at the onset of DN.
背景 糖尿病神经病变（DN）是糖尿病常见且痛苦的并发症，然而其发病机制尚不明确，临床治疗手段有限。本研究旨在探究雪旺细胞中过氧化物酶体在DN中的作用。
方法 采用激光共聚焦超分辨率成像和蛋白质印迹技术分析小鼠坐骨神经或雪旺细胞中过氧化物酶体的数量。利用RFP-GFP-SKL探针评估pexophagy（过氧化物酶体自噬）水平。采用酰基-树脂辅助捕获（acyl-RAC）实验和酰基-生物素交换（ABE）实验评估PEX11B的棕榈酰化修饰。此外，进行了孟德尔随机化（MR）分析以探究DN与多发性硬化（MS）之间潜在的因果关系。
结果 糖尿病小鼠坐骨神经中过氧化物酶体数量减少，而棕榈酸（PA）通过抑制雪旺细胞中的过氧化物酶体生物合成，诱导了过氧化物酶体数量的减少。机制上，PA诱导了PEX11B蛋白第25位半胱氨酸（C25）的棕榈酰化，破坏了其自身相互作用，并阻碍了过氧化物酶体的延伸。PPARα激动剂非诺贝特有效挽救了由PA引起的过氧化物酶体功能障碍，并恢复了糖尿病小鼠体内的过氧化物酶体数量。最后，MR分析表明，DN对MS存在显著的因果影响，且MS的发生和进展与过氧化物酶体功能障碍密切相关。
结论 靶向过氧化物酶体生物合成通路可能是预防和治疗DN的有效策略，同时强调了在DN发病初期关注MS风险的重要性。
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