PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy
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...
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2025-02-01
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| author | Yu Mei Yang Hang Bin Ma Yue Xiong Qian Wu Xiu Kui Gao |
| author_facet | Yu Mei Yang Hang Bin Ma Yue Xiong Qian Wu Xiu Kui Gao |
| author_sort | Yu Mei Yang |
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| description | 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. |
| format | Article |
| id | doaj-art-e9fa525cbb5e49418875fea5bb212a52 |
| institution | DOAJ |
| issn | 1423-0127 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-e9fa525cbb5e49418875fea5bb212a522025-08-20T02:43:13ZengBMCJournal of Biomedical Science1423-01272025-02-0132111710.1186/s12929-024-01115-5PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathyYu Mei Yang0Hang Bin Ma1Yue Xiong2Qian Wu3Xiu Kui Gao4Department of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang UniversityDepartment of Radiology, Center of Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang UniversityDepartment of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang UniversityDepartment of Radiology, Center of Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang UniversityDepartment of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang UniversityAbstract 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.https://doi.org/10.1186/s12929-024-01115-5Diabetic neuropathySchwann cellsPeroxisomesPalmitoylationMendelian randomizationMultiple sclerosis |
| spellingShingle | Yu Mei Yang Hang Bin Ma Yue Xiong Qian Wu Xiu Kui Gao PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy Journal of Biomedical Science Diabetic neuropathy Schwann cells Peroxisomes Palmitoylation Mendelian randomization Multiple sclerosis |
| title | PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy |
| title_full | PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy |
| title_fullStr | PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy |
| title_full_unstemmed | PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy |
| title_short | PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy |
| title_sort | pex11b palmitoylation couples peroxisomal dysfunction with schwann cells fail in diabetic neuropathy |
| topic | Diabetic neuropathy Schwann cells Peroxisomes Palmitoylation Mendelian randomization Multiple sclerosis |
| url | https://doi.org/10.1186/s12929-024-01115-5 |
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