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首页> 美国卫生研究院文献>The Journal of Neuroscience >Enhancing Mitochondrial Calcium Buffering Capacity Reduces Aggregation of Misfolded SOD1 and Motor Neuron Cell Death without Extending Survival in Mouse Models of Inherited Amyotrophic Lateral Sclerosis
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Enhancing Mitochondrial Calcium Buffering Capacity Reduces Aggregation of Misfolded SOD1 and Motor Neuron Cell Death without Extending Survival in Mouse Models of Inherited Amyotrophic Lateral Sclerosis

机译：增强线粒体钙缓冲能力减少遗传错误的肌萎缩性侧索硬化的小鼠模型中错误折叠的SOD1和运动神经元细胞死亡的聚集而不会延长生存期。

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Mitochondria have been proposed as targets for toxicity in amyotrophic lateral sclerosis (ALS), a progressive, fatal adult-onset neurodegenerative disorder characterized by the selective loss of motor neurons. A decrease in the capacity of spinal cord mitochondria to buffer calcium (Ca2+) has been observed in mice expressing ALS-linked mutants of SOD1 that develop motor neuron disease with many of the key pathological hallmarks seen in ALS patients. In mice expressing three different ALS-causing SOD1 mutants, we now test the contribution of the loss of mitochondrial Ca2+-buffering capacity to disease mechanism(s) by eliminating ubiquitous expression of cyclophilin D, a critical regulator of Ca2+-mediated opening of the mitochondrial permeability transition pore that determines mitochondrial Ca2+ content. A chronic increase in mitochondrial buffering of Ca2+ in the absence of cyclophilin D was maintained throughout disease course and was associated with improved mitochondrial ATP synthesis, reduced mitochondrial swelling, and retention of normal morphology. This was accompanied by an attenuation of glial activation, reduction in levels of misfolded SOD1 aggregates in the spinal cord, and a significant suppression of motor neuron death throughout disease. Despite this, muscle denervation, motor axon degeneration, and disease progression and survival were unaffected, thereby eliminating mutant SOD1-mediated loss of mitochondrial Ca2+ buffering capacity, altered mitochondrial morphology, motor neuron death, and misfolded SOD1 aggregates, as primary contributors to disease mechanism for fatal paralysis in these models of familial ALS.
机译：线粒体已被提议作为肌萎缩性侧索硬化症（ALS）毒性的靶点，肌萎缩性侧索硬化症是一种以运动神经元的选择性丧失为特征的进行性，致命的成人发作性神经退行性疾病。在表达ALS连锁的SOD1突变体的小鼠中观察到脊髓线粒体缓冲钙（Ca 2 + ）的能力降低，该突变体发展为运动神经元疾病，具有许多关键的病理学特征。 ALS患者。现在，在表达三种不同的导致ALS的SOD1突变体的小鼠中，通过消除普遍存在的亲环蛋白D的表达，我们测试了线粒体Ca 2 + 缓冲能力丧失对疾病机理的贡献Ca 2 + 介导的线粒体通透性过渡孔打开的调节剂，可确定线粒体Ca 2 + 的含量。在整个病程中，在不存在亲环蛋白D的情况下，Ca 2 + 的线粒体缓冲作用一直保持长期增加，并且与线粒体ATP合成的改善，线粒体肿胀的减少和形态的正常保留有关。这伴随着神经胶质激活的减弱，脊髓中错误折叠的SOD1聚集体水平的降低以及整个疾病中运动神经元死亡的显着抑制。尽管如此，肌肉神经支配，运动轴突变性以及疾病的进展和生存都没有受到影响，从而消除了突变型SOD1介导的线粒体Ca 2 + 缓冲能力的丧失，线粒体形态的改变，运动神经元的死亡和折叠错误SOD1聚集，作为这些家族性ALS模型中致命性瘫痪的疾病机理的主要贡献者。

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