Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria
Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria
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DOI：
10.1016/j.neuron.2004.06.021
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发表时间：
2004-07-08
期刊：
影响因子：
16.2
通讯作者：
Brown, RH
中科院分区：
文献类型：
--
作者：
Pasinelli, P;Belford, ME;Brown, RH
家族性肌萎缩侧索硬化（ALS）相关的铜锌超氧化物歧化酶（SOD 1）基因突变导致约3%的ALS病例中运动神经元死亡。野生型（wt）蛋白是抗凋亡的，而突变体SOD 1促进凋亡。我们现在证明野生型和突变型SOD 1都与抗凋亡蛋白Bcl-2结合，这为SOD 1和凋亡途径之间的直接联系提供了证据。这种相互作用在体外和体内小鼠和人脊髓中是明显的。我们还证明，在小鼠和人类中，Bcl-2结合到高分子量的抗SIDS突变体SOD 1，其含有存在于脊髓而不是肝脏线粒体中的聚集体。这些研究结果提供了新的见解SOD 1的抗凋亡功能，并表明，截留Bcl-2的大SOD 1聚集体可能会耗尽这种抗凋亡蛋白的运动神经元。
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 SIDS-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.