Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670, USA.
Neuron. 2010 Aug 26;67(4):575-87. doi: 10.1016/j.neuron.2010.07.019.
Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. This interaction is found on isolated spinal cord mitochondria and can be reconstituted with purified components in vitro. ADP passage through the outer membrane is diminished in spinal mitochondria from mutant SOD1-expressing ALS rats. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of individual channels when reconstituted in a lipid bilayer. Reduction of VDAC1 activity with targeted gene disruption is shown to diminish survival by accelerating onset of fatal paralysis in mice expressing the ALS-causing mutation SOD1(G37R). Taken together, our results establish a direct link between misfolded mutant SOD1 and mitochondrial dysfunction in this form of inherited ALS.
超氧化物歧化酶 1（SOD1）的突变导致肌萎缩侧索硬化症（ALS），这是一种以运动神经元丧失为特征的神经退行性疾病。我们现在使用构象特异性抗体证明，错误折叠的突变 SOD1 直接与电压依赖性阴离子通道（VDAC1）结合，VDAC1 是一种嵌入线粒体外膜的完整膜蛋白。这种相互作用在分离的脊髓线粒体中被发现，并且可以在体外与纯化的成分重新构成。突变 SOD1 表达 ALS 大鼠脊髓线粒体中通过外膜的 ADP 传递减少。当在脂质双层中重新构成时，突变 SOD1 与 VDAC1 的直接结合抑制单个通道的电导。通过靶向基因敲除减少 VDAC1 活性被证明可以通过加速表达 ALS 致病突变 SOD1（G37R）的小鼠致命瘫痪的发作来减少存活。总之，我们的结果在这种遗传性 ALS 中建立了错误折叠的突变 SOD1 与线粒体功能障碍之间的直接联系。
