Hatton Courtney L, Terrey Markus, Presa Maximiliano, Ryan Jennifer, Perkins Sara, Kennedy Vicki, Lutz Cathleen M, Burgess Robert W
The Jackson Laboratory, Bar Harbor, Maine, USA.
J Peripher Nerv Syst. 2025 Sep;30(3):e70052. doi: 10.1111/jns.70052.
Degeneration of peripheral motor and sensory axons is a key aspect of the pathophysiology of Charcot-Marie-Tooth disease and related inherited neurodegenerative conditions.
Given that mutations in many (> 100) genes can cause these disorders, it is unclear if a generalized therapeutic strategy can be identified that will apply across these disease subtypes; however, strategies to prevent or slow axon degeneration are attractive candidates. Wallerian axon degeneration is an active process following insults such as nerve injury, and SARM1 is a central mediator of this process. When SARM1 is inhibited, axons distal to the site of injury persist for weeks rather than degenerating. In addition, SARM1 inhibition or genetic deletion has been shown to provide benefit in acquired neuropathies such as diabetic/metabolic neuropathy and chemotherapy-induced neuropathy in animal models. Here we examined the effects of genetically deleting Sarm1 in mouse models of CMT.
We bred knockout mice lacking Sarm1 to three different mouse models of CMT or related disorders. These include mice lacking Gjb1, modeling CMT1X, mice with mutations in Kif1a, modeling hereditary sensory neuropathy IIC and spastic paraplegia type 30, and mice lacking Fig4, modeling CMT4J and Yunis-Varon syndrome. Clinically relevant outcomes measures including survival (Kif1a and Fig4), grip strength and motor behavior, peripheral neurophysiology, molecular biomarkers, and nerve histopathology were assessed for each model with and without Sarm1 expression.
No improvement in the mutant phenotype was found for any model, although elevated levels of circulating neurofilament light chain levels were delayed in the Fig4 mice. Kif1a mice showed deficits slightly earlier in the absence of Sarm1.
While we found no benefit from deleting Sarm1 in these mouse models, they were chosen for their human disease relevance and not for biochemical indicators that SARM1 may be a good target. Thus, SARM1 inhibition may still be effective in other forms of inherited neuropathy, but additional research will be required to identify those candidate subtypes.
外周运动和感觉轴突的退化是夏科-马里-图斯病及相关遗传性神经退行性疾病病理生理学的一个关键方面。
鉴于许多（>100个）基因的突变可导致这些疾病，目前尚不清楚是否能确定一种适用于这些疾病亚型的通用治疗策略；然而，预防或减缓轴突退化的策略是有吸引力的候选方案。华勒氏轴突退化是神经损伤等损伤后的一个活跃过程，而SARM1是这一过程的核心介质。当SARM1被抑制时，损伤部位远端的轴突会持续数周而不是退化。此外，在动物模型中，SARM1抑制或基因缺失已被证明对糖尿病/代谢性神经病变和化疗引起的神经病变等获得性神经病变有益。在此，我们研究了在夏科-马里-图斯病小鼠模型中基因敲除Sarm1的效果。
我们将缺乏Sarm1的基因敲除小鼠与三种不同的夏科-马里-图斯病或相关疾病小鼠模型进行杂交。这些模型包括缺乏Gjb1的小鼠（模拟CMT1X）、Kif1a发生突变的小鼠（模拟遗传性感觉神经病变IIC和30型痉挛性截瘫）以及缺乏Fig4的小鼠（模拟CMT4J和尤尼斯-瓦伦综合征）。对每个有或没有Sarm1表达的模型评估了包括生存（Kif1a和Fig4）、握力和运动行为、外周神经生理学、分子生物标志物以及神经组织病理学等临床相关结局指标。
尽管Fig4小鼠循环神经丝轻链水平升高的情况有所延迟，但未发现任何模型的突变表型有改善。Kif1a小鼠在没有Sarm1的情况下缺陷出现得稍早。
虽然我们发现在这些小鼠模型中敲除Sarm1没有益处，但选择这些模型是因为它们与人类疾病相关，而非基于SARM1可能是一个良好靶点的生化指标。因此，SARM1抑制在其他形式的遗传性神经病变中可能仍然有效，但需要更多研究来确定那些候选亚型。
