Haploinsufficiency of AFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration
Haploinsufficiency of AFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration
复制标题
DOI：
10.1523/jneurosci.1532-09.2009
复制
发表时间：
2009-07-22
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;Magnoni, Raffaella;Casari, Giorgio
Paraplegin和AFG 3L 2是普遍存在的核编码的线粒体蛋白，其在线粒体内膜中形成异源寡聚paraplegin-AFG 3L 2和同源寡聚AFG 3L 2复合物，称为AAA蛋白酶。这些复合物确保内膜中的蛋白质质量控制，以及对呼吸链复合物的伴侣样活性。尽管在同一复合物中共组装，paraplegin或AFG 3L 2的突变导致两种不同的神经退行性疾病。事实上，paraplegin的突变是遗传性痉挛性截瘫的隐性形式的原因，而AFG 3L 2的突变最近已与显性形式的脊髓小脑共济失调（SCA 28）相关。在这项工作中，我们报告了Afg 3l 2单倍不足的小鼠模型概括了人类疾病的重要病理生理学特征，从而代表了第一个SCA 28模型。此外，我们提出了一种发病机制，其中呼吸链功能障碍和活性氧产生增加引起的Afg 3l 2单倍不足导致暗变性的浦肯野细胞和小脑功能障碍。
Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, namedm-AAA proteases. These complexes ensure protein quality control in the inner membrane, jointly with a chaperone-like activity on the respiratory chain complexes. Despite coassembling in the same complex, mutations of either paraplegin or AFG3L2 cause two different neurodegenerative disorders. Indeed, mutations of paraplegin are responsible for a recessive form of hereditary spastic paraplegia, whereas mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28). In this work, we report that the mouse model haploinsufficient for Afg3l2 recapitulates important pathophysiological features of the human disease, thus representing the first SCA28 model. Furthermore, we propose a pathogenetic mechanism in which respiratory chain dysfunction and increased reactive oxygen species production caused by Afg3l2 haploinsufficiency lead to dark degeneration of Purkinje cells and cerebellar dysfunction.