Kshirsagar Aniket, Ronan Rachel, Rebelo Ana Lúcia, McMahon Siobhan, Pandit Abhay, Schlosser Gerhard
Research Ireland Centre for Medical Devices (CÚRAM), University of Galway, Biomedical Sciences Building, Newcastle Road, Galway, H91 W2TY, Ireland.
Anatomy, School of Medicine, University of Galway, Galway, Ireland.
Dev Biol. 2025 Mar;519:65-78. doi: 10.1016/j.ydbio.2024.12.009. Epub 2024 Dec 16.
Spinal cord injury in humans is a life-changing condition with no effective treatment. However, many non-mammalian vertebrates can fully regenerate their spinal cord after injury. Frogs such as Xenopus can regenerate the spinal cord at larval stages, but lose this capacity at metamorphosis. This makes them ideal models to elucidate molecular pathways underlying regenerative capacity by comparing responses to spinal cord injury in regenerative (R) and non-regenerative (NR) stages of the same species. Here we use quantitative proteomics with Isobaric Tags for Relative and Absolute Quantification (iTRAQ) followed by Ingenuity Pathway Analysis (IPA) to identify functions and pathways that were differentially regulated after spinal cord injury between R and NR stages in Xenopus laevis. We find that many embryonic pathways of neuronal development are re-activated following SCI at the R but not at the NR stage. This is accompanied by the upregulation of regulatory proteins controlling transcription and translation at the R stage, but their downregulation at the NR stage. Conversely, lipid hydrolysis and uptake as well as mitochondrial oxidative phosphorylation is downregulated at the R, but upregulated at the NR stage. Taken together this suggests that dysregulation of lipid homeostasis and augmentation of oxidative stress play a key role in the loss of regenerative capacity of the spinal cord after metamorphosis. In identifying new factors regulating regenerative capacity in the vertebrate spinal cord, our findings suggest new potential therapeutic targets for promoting neural repair in the injured adult mammalian spinal cord.
人类脊髓损伤是一种改变人生的疾病，目前尚无有效治疗方法。然而，许多非哺乳动物脊椎动物在脊髓损伤后能够完全再生。非洲爪蟾等青蛙在幼体阶段可以再生脊髓，但在变态发育后失去这种能力。这使得它们成为通过比较同一物种再生期（R）和非再生期（NR）对脊髓损伤的反应来阐明再生能力潜在分子途径的理想模型。在这里，我们使用带有相对和绝对定量等压标签（iTRAQ）的定量蛋白质组学，随后进行 Ingenuity 通路分析（IPA），以确定非洲爪蟾 R 期和 NR 期脊髓损伤后差异调节的功能和通路。我们发现，许多神经元发育的胚胎通路在 R 期脊髓损伤后重新激活，而在 NR 期则不然。这伴随着 R 期控制转录和翻译的调节蛋白上调，但在 NR 期下调。相反，脂质水解和摄取以及线粒体氧化磷酸化在 R 期下调，但在 NR 期上调。综上所述，这表明脂质稳态失调和氧化应激增加在变态发育后脊髓再生能力丧失中起关键作用。在确定调节脊椎动物脊髓再生能力的新因素时，我们的研究结果为促进成年哺乳动物脊髓损伤后的神经修复提出了新的潜在治疗靶点。
