Spongiform encephalopathy is an intriguing yet poorly understood neuropathology characterized by vacuoles, demyelination, and gliosis. It is observed in patients with prion disease, primary mitochondrial disease, HIV-1 infection of the brain, and some inherited disorders, but the underlying mechanism of disease remains unclear. The brains of mice lacking the MGRN1 E3 ubiquitin ligase develop vacuoles by 9 months of age. MGRN1-dependent ubiquitination has been reported to regulate mitofusin 1 and GP78, suggesting MGRN1 may have a direct effect on mitochondrial homeostasis. Here, we demonstrate that some MGRN1 localizes to mitochondria, most likely due to N-myristoylation, and mitochondria in cells from Mgrn1 null mutant mice display fragmentation and depolarization without recruitment of the parkin E3 ubiquitin ligase. The late onset of pathology in the brains of Mgrn1 null mutant mice suggests that a further, age-dependent effect on mitochondrial homeostasis may be required to trigger vacuolation. Parkin protein and mRNA levels showed a significant decline in the brains of Mgrn1 null mutant mice by 12 months of age. To test whether loss of parkin triggers vacuolation through a synergistic effect, we generated Mgrn1; parkin double mutant mice. By 1 month of age, their brains demonstrated more severe mitochondrial dysfunction than Mgrn1 null mutants, but there was no effect on the age-of-onset of spongiform neurodegeneration. Expression of the ATF4 transcription factor, a key regulator of the mitochondrial stress response, also declined in the brains of aged Mgrn1 null mutant mice. Together, the data presented here indicate that loss of MGRN1 has early, direct effects on mitochondrial homeostasis and late, indirect effects on the ability of cells to respond to mitochondrial stress.

中文翻译：

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海绵状神经变性相关的MGRN1 E3泛素连接酶对线粒体稳态的慢性和年龄依赖性。

海绵状脑病是一种有趣的神经病，但知之甚少，其特征在于空泡，脱髓鞘和神经胶质增生。在患有病毒病，原发性线粒体疾病，大脑的HIV-1感染和某些遗传性疾病的患者中观察到这种病，但该病的潜在机制仍不清楚。缺乏MGRN1 E3泛素连接酶的小鼠大脑在9个月大时会形成液泡。据报道，依赖MGRN1的泛素化调节线粒体蛋白1和GP78，这表明MGRN1可能对线粒体体内平衡具有直接作用。在这里，我们证明某些MGRN1定位于线粒体，最有可能是由于N-肉豆蔻酰化，而来自Mgrn1空突变小鼠的细胞中的线粒体却显示出碎片和去极化现象，而没有募集Parkin E3泛素连接酶。Mgrn1 null突变小鼠大脑中病理的晚期发作表明，可能需要对线粒体体内稳态的进一步的，年龄依赖性的影响才能触发空泡作用。到12个月大时，Mgrn1无突变小鼠的大脑中的帕金蛋白和mRNA水平显着下降。为了测试是否通过协同作用降低了Parkin是否触发了空泡形成，我们生成了Mgrn1；帕金双重突变小鼠。到1个月大时，他们的大脑显示出比Mgrn1空突变体更严重的线粒体功能障碍，但对海绵状神经变性的发病年龄没有影响。ATF4转录因子的表达，线粒体应激反应的关键调节器，也衰老的Mgrn1空突变小鼠的大脑中。总之，此处提供的数据表明MGRN1的丢失已经提前，