SARM1 detection in oligodendrocytes but not Schwann cells though sarm1/Sarm1 deletion does not perturb CNS nor PNS myelination in zebrafish and mice-猫眼课题宝

DOI：

10.1101/2022.12.08.519209

发表时间：

2022-12

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

S. V. Fazal;Clara Mutschler;C. Z. Chen;M. Turmaine;Chiung-Ya Chen;Y. Hsueh;Andrea Loreto;Ángeles Casillas-Bajo;H. Cabedo;R. Franklin;R. Barker;Kelly R. Monk;B. Steventon;Michael P. Coleman;J. Gómez-Sánchez;P. Arthur-Farraj

SARM 1是程序性轴突死亡的中央调节器，并且在神经系统受到创伤和毒性损伤后启动轴突自我破坏是必需的。这种轴突变性途径的异常激活越来越多地被认为是人类神经系统疾病的贡献者，SARM 1敲低或抑制已成为一种有吸引力的治疗策略，以在各种外周和中枢神经系统疾病中保护轴突损失。尽管如此，仍然不清楚Sarm 1/SARM 1是否存在于髓鞘形成胶质细胞中，以及它是否在PNS或CNS的髓鞘形成中发挥作用。重要的是要回答这些问题，以了解未来抑制SARM 1功能的疗法是否可能对髓鞘形成产生意外的有害影响。在这里，我们表明，Sarm 1 mRNA存在于斑马鱼的少突胶质细胞，但在斑马鱼和小鼠的雪旺细胞中仅以低水平检测到。我们发现SARM 1蛋白在小鼠少突胶质细胞中在体外和体内都很容易检测到，并且在少突胶质细胞中内源性SARM 1的激活诱导细胞死亡。相反，SARM 1蛋白在成年小鼠神经系统的雪旺细胞和卫星胶质细胞中检测不到。培养的雪旺细胞含有可忽略的功能性SARM 1，并且对特定的SARM 1激活剂不敏感。使用斑马鱼和小鼠Sarm 1突变体，我们表明，SARM 1是不需要启动髓鞘形成也不髓鞘维护少突胶质细胞和雪旺细胞。因此，在神经系统中抑制SARM 1功能以治疗神经系统疾病的策略不太可能干扰人类的髓鞘形成。在斑马鱼和小鼠中，少突胶质细胞（而不是雪旺细胞）对内源性SARM 1激活的反应中，少突胶质细胞（而不是雪旺细胞）死亡，CNS和PNS髓鞘形成受到sarm 1/Sarm 1缺失的阻碍。

SARM1 is a central regulator of programmed axon death and is required to initiate axon self-destruction after traumatic and toxic insults to the nervous system. Abnormal activation of this axon degeneration pathway is increasingly recognized as a contributor to human neurological disease and SARM1 knockdown or inhibition has become an attractive therapeutic strategy to preserve axon loss in a variety of disorders of the peripheral and central nervous system. Despite this, it remains unknown whether Sarm1/SARM1 is present in myelinating glia and whether it plays a role in myelination in the PNS or CNS. It is important to answer these questions to understand whether future therapies inhibiting SARM1 function may have unintended deleterious impacts on myelination. Here we show that Sarm1 mRNA is present in oligodendrocytes in zebrafish but only detectable at low levels in Schwann cells in both zebrafish and mice. We find SARM1 protein is readily detectable in murine oligodendrocytes in vitro and in vivo and activation of endogenous SARM1 in oligodendrocytes induces cell death. In contrast, SARM1 protein is not detectable in Schwann cells and satellite glia in the adult murine nervous system. Cultured Schwann cells contain negligible functional SARM1 and are insensitive to specific SARM1 activators. Using zebrafish and mouse Sarm1 mutants, we show that SARM1 is not required for initiation of myelination nor myelin sheath maintenance by oligodendrocytes and Schwann cells. Thus, strategies to inhibit SARM1 function in the nervous system to treat neurological disease are unlikely to perturb myelination in humans. Main Points SARM1 protein is detectable in oligodendrocytes but not in Schwann cells Oligodendrocytes but not Schwann cells die in response to endogenous SARM1 activation CNS nor PNS myelination, in zebrafish and mice, is hindered by loss of sarm1/Sarm1

SARM1 detection in oligodendrocytes but not Schwann cells though sarm1/Sarm1 deletion does not perturb CNS nor PNS myelination in zebrafish and mice

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