SARM1 detection in myelinating glia: sarm1/Sarm1 is dispensable for PNS and CNS myelination in zebrafish and mice.
SARM1 detection in myelinating glia: sarm1/Sarm1 is dispensable for PNS and CNS myelination in zebrafish and mice.
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DOI：
10.3389/fncel.2023.1158388
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发表时间：
2023
影响因子：
5.3
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中科院分区：
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自从在人类神经系统疾病中发现 SARM1 突变以来，SARM1 抑制已成为一种有吸引力的治疗策略，可以在各种外周 (PNS) 和中枢神经系统 (CNS) 疾病中保护轴突。虽然 SARM1 已在神经元中得到广泛研究，但 SARM1 是否存在于髓鞘神经胶质细胞中并发挥功能仍不清楚？这是一个需要解决的重要问题。首先，确定神经系统中其他细胞类型的 SARM1 功能障碍是否可能导致 SARM1 依赖性疾病的神经病理学？其次，确定改变 SARM1 功能的疗法是否可能对 PNS 或 CNS 髓鞘形成产生意想不到的有害影响？令人惊讶的是，我们发现斑马鱼脊髓中的少突胶质细胞表达 sarm1 mRNA，并且在体外和体内啮齿动物少突胶质细胞中很容易检测到 SARM1 蛋白。此外，培养的少突胶质细胞中内源性 SARM1 的激活会诱导细胞快速死亡。相比之下，在外周神经胶质细胞中，在体内雪旺细胞和卫星胶质细胞中检测不到 SARM1 蛋白，并且在雪旺细胞、斑马鱼和小鼠体内检测到 sarm1/Sarm1 mRNA 的水平非常低。将特定的 SARM1 激活剂应用于培养的小鼠施万细胞不会诱导细胞死亡，并且烟酰胺腺嘌呤二核苷酸 (NAD) 水平保持不变，表明施万细胞可能不含有功能相关水平的 SARM1。最后，我们解决了髓鞘形成或髓磷脂维持是否需要 SARM1 的问题。在斑马鱼和小鼠 PNS 和 CNS 中，我们发现 SARM1 不是髓鞘形成起始所必需的，并且成年小鼠神经系统中髓鞘的维持不受影响。因此，抑制 SARM1 功能来治疗神经系统疾病的策略不太可能扰乱人类的髓鞘形成。
Since SARM1 mutations have been identified in human neurological disease, SARM1 inhibition has become an attractive therapeutic strategy to preserve axons in a variety of disorders of the peripheral (PNS) and central nervous system (CNS). While SARM1 has been extensively studied in neurons, it remains unknown whether SARM1 is present and functional in myelinating glia? This is an important question to address. Firstly, to identify whether SARM1 dysfunction in other cell types in the nervous system may contribute to neuropathology in SARM1 dependent diseases? Secondly, to ascertain whether therapies altering SARM1 function may have unintended deleterious impacts on PNS or CNS myelination? Surprisingly, we find that oligodendrocytes express sarm1 mRNA in the zebrafish spinal cord and that SARM1 protein is readily detectable in rodent oligodendrocytes in vitro and in vivo. Furthermore, activation of endogenous SARM1 in cultured oligodendrocytes induces rapid cell death. In contrast, in peripheral glia, SARM1 protein is not detectable in Schwann cells and satellite glia in vivo and sarm1/Sarm1 mRNA is detected at very low levels in Schwann cells, in vivo, in zebrafish and mouse. Application of specific SARM1 activators to cultured mouse Schwann cells does not induce cell death and nicotinamide adenine dinucleotide (NAD) levels remain unaltered suggesting Schwann cells likely contain no functionally relevant levels of SARM1. Finally, we address the question of whether SARM1 is required for myelination or myelin maintenance. In the zebrafish and mouse PNS and CNS, we show that SARM1 is not required for initiation of myelination and myelin sheath maintenance is unaffected in the adult mouse nervous system. Thus, strategies to inhibit SARM1 function to treat neurological disease are unlikely to perturb myelination in humans.