Dept. of Neurology, Friedrich-Schiller University Hospital Jena, Erlanger Allee 101, 07747 Jena, Germany.
Cell Calcium. 2010 Feb;47(2):165-74. doi: 10.1016/j.ceca.2009.12.002. Epub 2010 Jan 29.
In the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS), motor neurons degenerate with signs of organelle fragmentation, free radical damage, mitochondrial Ca2+ overload, impaired axonal transport and accumulation of proteins in intracellular inclusion bodies. Subgroups of motor neurons of the brainstem and the spinal cord expressing low amounts of Ca2+ buffering proteins are particularly vulnerable. In ALS, chronic excitotoxicity mediated by Ca2+-permeable AMPA type glutamate receptors seems to initiate a self-perpetuating process of intracellular Ca2+ dysregulation with consecutive endoplasmic reticulum Ca2+ depletion and mitochondrial Ca2+ overload. The only known effective treatment, riluzole, seems to reduce glutamatergic input. This review introduces the hypothesis of a "toxic shift of Ca2+" within the endoplasmic reticulum-mitochondria Ca2+ cycle (ERMCC) as a key mechanism in motor neuron degeneration, and discusses molecular targets which may be of interest for future ERMCC modulating neuroprotective therapies.
在致命的神经退行性疾病肌萎缩侧索硬化症（ALS）中，运动神经元退化伴随着细胞器碎片化、自由基损伤、线粒体 Ca2+超载、轴突运输受损以及细胞内包涵体中蛋白质积累的迹象。表达低水平 Ca2+缓冲蛋白的脑干和脊髓运动神经元亚群特别容易受到影响。在 ALS 中，由 Ca2+通透性 AMPA 型谷氨酸受体介导的慢性兴奋性毒性似乎会引发细胞内 Ca2+失调的自我维持过程，随后是内质网 Ca2+耗竭和线粒体 Ca2+超载。唯一已知的有效治疗方法利鲁唑似乎可以减少谷氨酸能输入。这篇综述介绍了内质网-线粒体 Ca2+循环（ERMCC）内“Ca2+毒性转移”的假说，作为运动神经元退化的关键机制，并讨论了可能对未来 ERMCC 调节神经保护治疗有兴趣的分子靶点。
