Genzyme Corporation, 49 New York Ave., Framingham, MA 01701-9322, USA.
FASEB J. 2011 Dec;25(12):4369-77. doi: 10.1096/fj.11-190819. Epub 2011 Aug 29.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron cell loss, muscular atrophy, and a shortened life span. Survival is highly variable, as some patients die within months, while others live for many years. Exposure to stress or the development of a nonoptimal stress response to disease might account for some of this variability. We show in the SOD1(G93A) mouse model of ALS that recurrent exposure to restraint stress led to an earlier onset of astrogliosis and microglial activation within the spinal cord, accelerated muscular weakness, and a significant decrease in median survival (105 vs. 122 d) when compared to nonstressed animals. Moreover, during normal disease course, ALS mice display a cacostatic stress response by developing an aberrant serum corticosterone circadian rhythm. Interestingly, we also found that higher corticosterone levels were significantly correlated with both an earlier onset of paralysis (males: r(2)=0.746; females: r(2)=0.707) and shorter survival times (males: r(2)=0.680; females: r(2)=0.552) in ALS mice. These results suggest that stress is capable of accelerating disease progression and that strategies that modulate glucocorticoid metabolism might be a viable treatment approach for ALS.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征是运动神经元细胞丢失、肌肉萎缩和寿命缩短。生存率差异很大，有些患者在数月内死亡，而有些患者则可以存活多年。应激暴露或疾病产生非最优应激反应可能是造成这种差异的部分原因。我们在 SOD1(G93A)ALS 小鼠模型中显示，反复暴露于束缚应激会导致脊髓内星形胶质细胞和小胶质细胞的激活更早出现，肌肉无力加速，并导致中位生存时间显著缩短（105 天对 122 天），与未受应激的动物相比。此外，在正常疾病过程中，ALS 小鼠通过产生异常的血清皮质酮昼夜节律表现出代谢性应激反应。有趣的是，我们还发现较高的皮质酮水平与 ALS 小鼠瘫痪的更早发作（雄性：r(2)=0.746；雌性：r(2)=0.707）和生存时间缩短（雄性：r(2)=0.680；雌性：r(2)=0.552）显著相关。这些结果表明，应激能够加速疾病进展，而调节糖皮质激素代谢的策略可能是 ALS 的一种可行治疗方法。
