Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
Institute of Neuropathology, University of Zurich, Zurich, Switzerland
J Exp Med. 2019 Apr 1;216(4):743-756. doi: 10.1084/jem.20171885. Epub 2019 Mar 6.
SARM1 (sterile α and HEAT/armadillo motif-containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family, which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. This deleterious effect was not due to SARM1-dependent modulation of prion-induced neuroinflammation, since microglial activation, astrogliosis, and brain cytokine profiles were not altered by SARM1 deficiency. Whole-transcriptome analyses indicated that SARM1 deficiency led to strong, selective overexpression of the pro-apoptotic gene XAF1 (X-linked inhibitor of apoptosis-associated factor 1). Consequently, the activity of pro-apoptotic caspases and neuronal death were enhanced in prion-infected mice. These results point to an unexpected function of SARM1 as a regulator of prion-induced neurodegeneration and suggest that XAF1 might constitute a therapeutic target in prion disease.
SARM1（无菌α和热/盔蛋白重复序列包含蛋白）是 MyD88（髓样分化初级反应基因 88）家族的一员，介导先天免疫反应。由于 SARM1 的失活可防止各种形式的轴突变性，我们测试了它是否可能预防朊病毒诱导的神经毒性。相反，我们发现 SARM1 缺乏会加剧朊病毒发病机制的进展。这种有害影响不是由于 SARM1 依赖性调节朊病毒诱导的神经炎症所致，因为 SARM1 缺乏不会改变小胶质细胞激活、星形胶质细胞增生和大脑细胞因子谱。全转录组分析表明，SARM1 缺乏导致促凋亡基因 XAF1（X 连锁凋亡抑制因子相关因子 1）的强烈、选择性过表达。因此，在朊病毒感染的小鼠中，促凋亡半胱氨酸酶的活性和神经元死亡增强。这些结果表明 SARM1 具有意想不到的功能，可作为朊病毒诱导的神经退行性变的调节剂，并表明 XAF1 可能是朊病毒病的治疗靶点。
