肌萎缩侧索硬化症相关的超氧化物歧化酶1突变蛋白与脊髓线粒体中的Bcl-2结合并聚集。

Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria.

作者信息

Pasinelli Piera, Belford Mary Elizabeth, Lennon Niall, Bacskai Brian J, Hyman Bradley T, Trotti Davide, Brown Robert H

机构信息

Day Laboratory for Neuromuscular Research, Department of Neurology, Harvard Medical School, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA.

出版信息

Neuron. 2004 Jul 8;43(1):19-30. doi: 10.1016/j.neuron.2004.06.021.

DOI:10.1016/j.neuron.2004.06.021

PMID:15233914

Abstract

Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis. We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord. We also demonstrate that in mice and humans, Bcl-2 binds to high molecular weight SDS-resistant mutant SOD1 containing aggregates that are present in mitochondria from spinal cord but not liver. These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein.

摘要

铜锌超氧化物歧化酶（SOD1）基因中的家族性肌萎缩侧索硬化症（ALS）相关突变在约3%的ALS病例中导致运动神经元死亡。野生型（wt）蛋白具有抗凋亡作用，而突变型SOD1则促进细胞凋亡。我们现在证明，wt和突变型SOD1均与抗凋亡蛋白Bcl-2结合，这为SOD1与凋亡途径之间的直接联系提供了证据。这种相互作用在小鼠和人类脊髓的体外和体内实验中均很明显。我们还证明，在小鼠和人类中，Bcl-2与高分子量、耐十二烷基硫酸钠（SDS）的突变型SOD1结合，该突变型SOD1含有存在于脊髓而非肝脏线粒体中的聚集体。这些发现为SOD1的抗凋亡功能提供了新的见解，并表明大的SOD1聚集体对Bcl-2的截留可能使运动神经元中的这种抗凋亡蛋白耗竭。