Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1G93A mouse model of ALS
Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1G93A mouse model of ALS
复制标题
DOI：
10.1111/j.1471-4159.2008.05595.x
复制
发表时间：
2008-10-01
影响因子：
4.7
通讯作者：
Greensmith, Linda
中科院分区：
文献类型：
--
作者：
Kalmar, Bernadett;Novoselov, Sergey;Greensmith, Linda
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征在于运动神经元变性，通常在诊断后1-5年内导致肌肉麻痹和死亡。虽然ALS的发病机制尚不清楚，但有证据表明蛋白酶体功能障碍和热休克蛋白参与了该疾病。我们之前已经证明，用称为arimoclomol的热休克反应的共诱导剂治疗在ALS的SODG 93 A小鼠模型中是有效的，延迟了疾病进展并延长了SODG 93 A小鼠的寿命（Kieran等人，2004）。然而，这项先前的研究仅检查了在疾病的症状前或早期阶段开始治疗时arimoclomol的效果。显然，为了使大多数ALS患者受益，任何治疗都必须在症状发作后有效。为了确定用arimoclomol进行症状后治疗是否有效，在本研究中，我们对SODG 93 A小鼠中的不同治疗方案进行了系统评估。从早期（75天）或晚期（90天）症状阶段用arimoclomol治疗显著改善了肌肉功能。从75天开始的治疗也显著增加了SODG 93 A小鼠的寿命，尽管从90天开始的治疗对寿命没有显著影响。arimoclomol的作用机制涉及热休克反应的增强，并且用arimoclomol处理增加Hsp 70表达。有趣的是，Hsp 70的这种上调伴随着经治疗的SODG 93 A小鼠脊髓中泛素阳性聚集体数量的减少，表明arimoclomol直接影响蛋白质聚集和降解。
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motoneuron degeneration, resulting in muscle paralysis and death, typically within 1-5 years of diagnosis. Although the pathogenesis of ALS remains unclear, there is evidence for the involvement of proteasome dysfunction and heat shock proteins in the disease. We have previously shown that treatment with a co-inducer of the heat shock response called arimoclomol is effective in the SODG93A mouse model of ALS, delaying disease progression and extending the lifespan of SODG93A mice (Kieran et al. 2004). However, this previous study only examined the effects arimoclomol when treatment was initiated in pre- or early symptomatic stages of the disease. Clearly, to be of benefit to the majority of ALS patients, any therapy must be effective after symptom onset. In order to establish whether post-symptomatic treatment with arimoclomol is effective, in this study we carried out a systematic assessment of different treatment regimes in SODG93A mice. Treatment with arimoclomol from early (75 days) or late (90 days) symptomatic stages significantly improved muscle function. Treatment from 75 days also significantly increased the lifespan of SODG93A mice, although treatment from 90 days has no significant effect on lifespan. The mechanism of action of arimoclomol involves potentiation of the heat shock response, and treatment with arimoclomol increased Hsp70 expression. Interestingly, this up-regulation in Hsp70 was accompanied by a decrease in the number of ubiquitin-positive aggregates in the spinal cord of treated SODG93A mice, suggesting that arimoclomol directly effects protein aggregation and degradation.