Martinelli Paola, La Mattina Veronica, Bernacchia Andrea, Magnoni Raffaella, Cerri Federica, Cox Gregory, Quattrini Angelo, Casari Giorgio, Rugarli Elena I
Division of Biochemistry and Genetics, Istituto Neurologico C. Besta, Milan, Italy.
Hum Mol Genet. 2009 Jun 1;18(11):2001-13. doi: 10.1093/hmg/ddp124. Epub 2009 Mar 16.
The mitochondrial m-AAA protease has a crucial role in axonal development and maintenance. Human mitochondria possess two m-AAA protease isoenzymes: a hetero-oligomeric complex, composed of paraplegin and AFG3L2 (Afg3 like 2), and a homo-oligomeric AFG3L2 complex. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons. Spg7(-/-) mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. In contrast, Afg3l2(Emv66/Emv66) mutant mice, lacking the AFG3L2 protein, are affected by a severe neuromuscular phenotype, due to defects in motor axon development. The role of the homo-oligomeric m-AAA protease and the extent of cooperation and redundancy between the two isoenzymes in adult neurons are still unclear. Here we report an early-onset severe neurological phenotype in Spg7(-/-) Afg3l2(Emv66/+) mice, characterized by loss of balance, tremor and ataxia. Spg7(-/-) Afg3l2(Emv66/+) mice display acceleration and worsening of the axonopathy observed in paraplegin-deficient mice. In addition, they show prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues are prone to lose mt-DNA and have unstable respiratory complexes. At late stages, neurons contain structural abnormal mitochondria defective in COX-SDH reaction. Our data demonstrate genetic interaction between the m-AAA isoenzymes and suggest that different neuronal populations have variable thresholds of susceptibility to reduced levels of the m-AAA protease. Moreover, they implicate impaired mitochondrial proteolysis as a novel pathway in cerebellar degeneration.
线粒体m-AAA蛋白酶在轴突发育和维持中起关键作用。人类线粒体拥有两种m-AAA蛋白酶同工酶：一种由痉挛素和AFG3L2（Afg3样蛋白2）组成的异源寡聚复合物，以及一种同源寡聚AFG3L2复合物。痉挛素（由SPG7基因编码）功能丧失会导致遗传性痉挛性截瘫，这是一种以皮质运动轴突逆行性退变为特征的疾病。Spg7(-/-)小鼠表现出长脊髓和外周轴突的迟发性退变以及异常线粒体的积累。相比之下，缺乏AFG3L2蛋白的Afg3l2(Emv66/Emv66)突变小鼠由于运动轴突发育缺陷而受到严重的神经肌肉表型影响。同源寡聚m-AAA蛋白酶的作用以及这两种同工酶在成年神经元中的合作和冗余程度仍不清楚。在此，我们报告了Spg7(-/-) Afg3l2(Emv66/+)小鼠出现的早发性严重神经表型，其特征为平衡失调、震颤和共济失调。Spg7(-/-) Afg3l2(Emv66/+)小鼠表现出在痉挛素缺陷小鼠中观察到的轴突病加速和恶化。此外，它们表现出明显的小脑退变，浦肯野细胞和平行纤维丢失，以及反应性星形胶质细胞增生。受影响组织中的线粒体容易丢失线粒体DNA且呼吸复合物不稳定。在晚期，神经元含有在COX-SDH反应中存在缺陷的结构异常线粒体。我们的数据证明了m-AAA同工酶之间的遗传相互作用，并表明不同的神经元群体对m-AAA蛋白酶水平降低具有可变的易感性阈值。此外，它们暗示线粒体蛋白水解受损是小脑退变的一条新途径。
