The mitochondrial protease AFG3L2 is essential for axonal development
The mitochondrial protease AFG3L2 is essential for axonal development
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DOI：
10.1523/jneurosci.4677-07.2008
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发表时间：
2008-03-12
影响因子：
5.3
通讯作者：
Casari, Giorgio
中科院分区：
文献类型：
--
作者：
Maltecca, Francesca;Aghaie, Asadollah;Casari, Giorgio
线粒体金属蛋白酶AFG3L2与同源蛋白parplegin形成超复合体，负责线粒体内必需的蛋白质质量控制。截瘫基因突变会导致上运动神经元的特殊轴突变性，从而导致遗传性痉挛性截瘫。在这里，我们介绍了两个Afg3l2小鼠模型：一个是新开发的空突变，另一个是我们发现的错义突变携带者的自发突变。与截瘫基因缺陷小鼠轻度和迟发性轴突变性相比，Afg3l2模型显示出明显的轴突发育障碍，髓鞘形成延迟，轴突径向生长不良，导致P16死亡。AFG3L2突变体的严重程度增加是由于AFG3L2不同于Parplegin的两个主要分子特征：它有更高的神经元表达，以及它具有支持异源寡聚和同源寡聚的多种能力。我们的数据表明AFG3L2通过连接线粒体新陈代谢和轴突发育发挥关键作用。此外，我们建议AFG3L2作为早期发病原因不明的运动神经元和小脑疾病的极佳候选。
The mitochondrial metalloprotease AFG3L2 assembles with the homologous protein paraplegin to form a supracomplex in charge of the essential protein quality control within mitochondria. Mutations of paraplegin cause a specific axonal degeneration of the upper motoneuron and, therefore, hereditary spastic paraplegia. Here we present two Afg3l2 murine models: a newly developed null and a spontaneous mutant that we found carrier of a missense mutation. Contrasting with the mild and late onset axonal degeneration of paraplegin-deficient mouse, Afg3l2 models display a marked impairment of axonal development with delayed myelination and poor axonal radial growth leading to lethality at P16. The increased severity of the Afg3l2 mutants is explained by two main molecular features that differentiate AFG3L2 from paraplegin: its higher neuronal expression and its versatile ability to support both hetero-oligomerization and homo-oligomerization. Our data assign to AFG3L2 a crucial role by linking mitochondrial metabolism and axonal development. Moreover, we propose AFG3L2 as an excellent candidate for motoneuron and cerebellar diseases with early onset unknown etiology.