We analyzed Trim2A/A mice, generated by CRISPR-Cas9, which have a recessive, null mutation of Trim2. Trim2A/A 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 (Trim2C/C), which has a partial deletion in the RING domain that is needed for ubiquitin ligase activity. Both the Trim2Aand the Trim2C alleles encode mutant TRIM2 proteins with reduced ubiquitination activity. In sum, Trim2A/A 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.

中文翻译：

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隐性Trim2突变在小鼠中引起轴突神经病。

我们分析了由CRISPR-Cas9产生的Trim2A / A小鼠，它们具有Trim2的隐性无效突变。Trim2A / A小鼠发生共济失调，这与小脑浦肯野细胞的严重丧失和周围神经病变有关。中枢神经系统的髓鞘轴突，包括小脑深核中的轴突，具有包括线粒体和神经丝在内的局部增大。在PNS中，髓鞘轴突缺失，特别是在最远端的神经中。受病理影响的神经元种群-初级感觉和运动神经元以及小脑Purkinje细胞-表达TRIM2，表明这些神经元中TRIM2的丧失导致其轴突的细胞自主效应。相比之下，在第二批Trim2突变小鼠（Trim2C / C）中找不到这些病理发现，泛素连接酶活性所需的RING域中有部分缺失。Trim2A和Trim2C等位基因均编码具有降低的泛素化活性的突变TRIM2蛋白。总而言之，Trim2A / A小鼠是人类隐性轴突神经病的遗传学真实动物模型，显然其功能不依赖于泛素连接酶活性。