Department of Neurology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Microbiology and Immunology, UIC College of Medicine, Chicago, IL, USA.
Neurobiol Dis. 2020 Jul;140:104845. doi: 10.1016/j.nbd.2020.104845. Epub 2020 Mar 20.
We analyzed Trim2 mice, generated by CRISPR-Cas9, which have a recessive, null mutation of Trim2. Trim2 mice develop ataxia that is associated with a severe loss of cerebellar Purkinje cells and a peripheral neuropathy. Myelinated axons in the CNS, including those in the deep cerebellar nuclei, have focal enlargements that contain mitochondria and neurofilaments. In the PNS, there is a loss of myelinated axons, particularly in the most distal nerves. The pathologically affected neuronal populations - primary sensory and motor neurons as well as cerebellar Purkinje cells - express TRIM2, suggesting that loss of TRIM2 in these neurons results in cell autonomous effects on their axons. In contrast, these pathological findings were not found in a second strain of Trim2 mutant mice (Trim2), which has a partial deletion in the RING domain that is needed for ubiquitin ligase activity. Both the Trim2and the Trim2 alleles encode mutant TRIM2 proteins with reduced ubiquitination activity. In sum, Trim2 mice are a genetically authentic animal model of a recessive axonal neuropathy of humans, apparently for a function that does not depend on the ubiquitin ligase activity.
我们分析了 Trim2 敲除小鼠，这些小鼠是通过 CRISPR-Cas9 技术产生的，它们携带 Trim2 的隐性纯合缺失突变。Trim2 敲除小鼠表现出共济失调，这与小脑浦肯野细胞的严重缺失和周围神经病变有关。中枢神经系统的髓鞘轴突，包括深部小脑核中的髓鞘轴突，有局灶性扩大，包含线粒体和神经丝。在周围神经系统中，有髓鞘轴突的丢失，特别是在最远端的神经中。病理性受影响的神经元群体 - 感觉和运动神经元以及小脑浦肯野细胞 - 表达 TRIM2，表明这些神经元中 TRIM2 的缺失导致其轴突的细胞自主效应。相比之下，在第二种 Trim2 突变小鼠（Trim2）中没有发现这些病理发现，该小鼠的 RING 结构域存在部分缺失，这是泛素连接酶活性所必需的。Trim2 和 Trim2 等位基因都编码具有降低泛素化活性的突变 TRIM2 蛋白。总之，Trim2 敲除小鼠是人类隐性轴索性神经病的一种遗传上真实的动物模型，显然是因为一种不依赖于泛素连接酶活性的功能。
