INSERM-Avenir Team, The Mediterranean Institute of Neurobiology, 13273 Marseille, France.
J Neurosci. 2012 Apr 4;32(14):4901-12. doi: 10.1523/JNEUROSCI.5431-11.2012.
Cellular responses to protein misfolding are thought to play key roles in triggering neurodegeneration. In the mutant superoxide dismutase (mSOD1) model of amyotrophic lateral sclerosis (ALS), subsets of motoneurons are selectively vulnerable to degeneration. Fast fatigable motoneurons selectively activate an endoplasmic reticulum (ER) stress response that drives their early degeneration while a subset of mSOD1 motoneurons show exacerbated sensitivity to activation of the motoneuron-specific Fas/NO pathway. However, the links between the two mechanisms and the molecular basis of their cellular specificity remained unclear. We show that Fas activation leads, specifically in mSOD1 motoneurons, to reductions in levels of calreticulin (CRT), a calcium-binding ER chaperone. Decreased expression of CRT is both necessary and sufficient to trigger SOD1(G93A) motoneuron death through the Fas/NO pathway. In SOD1(G93A) mice in vivo, reductions in CRT precede muscle denervation and are restricted to vulnerable motor pools. In vitro, both reduced CRT and Fas activation trigger an ER stress response that is restricted to, and required for death of, vulnerable SOD1(G93A) motoneurons. Our data reveal CRT as a critical link between a motoneuron-specific death pathway and the ER stress response and point to a role of CRT levels in modulating motoneuron vulnerability to ALS.
细胞对蛋白质错误折叠的反应被认为在引发神经退行性变中起关键作用。在肌萎缩侧索硬化症（ALS）的突变超氧化物歧化酶（mSOD1）模型中，运动神经元的亚群选择性地易发生变性。快速易疲劳的运动神经元选择性地激活内质网（ER）应激反应，导致其早期变性，而一部分 mSOD1 运动神经元对激活运动神经元特异性 Fas/NO 途径表现出过度敏感。然而，这两种机制之间的联系及其细胞特异性的分子基础仍不清楚。我们表明，Fas 的激活导致内质网钙结合伴侣钙网蛋白（CRT）的水平降低，这一现象在 mSOD1 运动神经元中是特异性的。CRT 表达水平的降低是通过 Fas/NO 途径引发 SOD1(G93A)运动神经元死亡所必需和充分的条件。在体内 SOD1(G93A)小鼠中，CRT 的减少先于肌肉失神经支配，并且仅限于易损的运动池。在体外，CRT 的减少和 Fas 的激活都触发了一种 ER 应激反应，这种反应仅限于并需要易损的 SOD1(G93A)运动神经元的死亡。我们的数据揭示了 CRT 作为一种运动神经元特异性死亡途径和 ER 应激反应之间的关键联系，并指出 CRT 水平在调节运动神经元对 ALS 的易感性方面的作用。
