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脊髓损伤后缺乏GlcNAc6ST1和GlcNAc6ST4的小鼠运动功能恢复增强。

Enhanced locomotor recovery in mice lacking GlcNAc6ST1 and GlcNAc6ST4 following spinal cord injury.

作者信息

Morozumi Masayoshi, Ozaki Tomoya, Nishitsuji Kazuchika, Takeda-Uchimura Yoshiko, Matsumoto Akiyuki, Ito Sadayuki, Imagama Shiro, Ishiguro Naoki, Yagi Hirokazu, Kato Koichi, Akama Tomoya O, Kosugi Tomoki, Maruyama Shoichi, Kadomatsu Kenji, Rosen Steven D, Noble-Haeusslein Linda J, Uchimura Kenji

机构信息

Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

出版信息

Life Sci Alliance. 2025 Aug 28;8(11). doi: 10.26508/lsa.202503469. Print 2025 Nov.

DOI:10.26508/lsa.202503469
PMID:40876929
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12394907/
Abstract

Spinal cord injury (SCI) damages neural circuits and triggers pro-inflammatory responses, resulting in locomotor impairment. The carbohydrate sulfotransferases GlcNAc6ST1 and GlcNAc6ST4 modulate the function of blood monocytes and microglia. However, their specific roles and enzymatic relationships in neuroinflammation and functional recovery after SCI remain unclear. In this study, we demonstrate that mice deficient in both GlcNAc6ST1 and GlcNAc6ST4 (DKO) exhibit improved locomotor recovery compared with mice with a single deficiency. DKO mice exhibit reduced levels of monocytes and activated macrophages/microglia at the injury site alongside increased serotonergic neural fibers, indicating enhanced neural plasticity. RNA sequencing reveals down-regulation of collagen I genes and up-regulation of genes encoding synaptic membrane components in the injured DKO spinal cord. In addition, GALAXY glycomic analysis shows an absence of GlcNAc-6-sulfated -glycans in the DKO spinal cord. These results suggest that GlcNAc6ST1 and GlcNAc6ST4 play complementary roles in promoting detrimental inflammatory responses post-SCI. Targeting these sulfotransferases could offer a novel therapeutic strategy to improve locomotor recovery after SCI.

摘要

脊髓损伤（SCI）会损害神经回路并引发促炎反应，导致运动功能障碍。碳水化合物磺基转移酶GlcNAc6ST1和GlcNAc6ST4调节血液单核细胞和小胶质细胞的功能。然而，它们在SCI后的神经炎症和功能恢复中的具体作用及酶促关系仍不清楚。在本研究中，我们证明，与单基因缺陷小鼠相比，同时缺乏GlcNAc6ST1和GlcNAc6ST4的双基因敲除（DKO）小鼠表现出更好的运动功能恢复。DKO小鼠损伤部位的单核细胞以及活化的巨噬细胞/小胶质细胞水平降低，同时5-羟色胺能神经纤维增加，表明神经可塑性增强。RNA测序显示，在损伤的DKO脊髓中，I型胶原蛋白基因下调，而编码突触膜成分的基因上调。此外，GALAXY糖组学分析显示，DKO脊髓中不存在GlcNAc-6-硫酸化聚糖。这些结果表明，GlcNAc6ST1和GlcNAc6ST4在促进SCI后有害的炎症反应中发挥互补作用。靶向这些磺基转移酶可能为改善SCI后的运动功能恢复提供一种新的治疗策略。

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Time-resolved single-cell RNAseq profiling identifies a novel subpopulation of inflammatory myeloid cells with delayed cytotoxic profile in chronic spinal cord injury.
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