Pre-symptomatic detection of chronic motor deficits and genotype prediction in congenic B6.SOD1(G93A) ALS mouse model.
Pre-symptomatic detection of chronic motor deficits and genotype prediction in congenic B6.SOD1(G93A) ALS mouse model.
复制标题
先天性B6.SOD1（G93A）ALS小鼠模型中慢性运动缺陷和基因型预测的症状前检测。
DOI：
10.1016/j.neuroscience.2009.08.031
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发表时间：
2009-12-15
期刊：
影响因子：
3.3
通讯作者：
Gonzalez-Lima, F.
中科院分区：
文献类型：
--
作者：
Hayworth, C. R.;Gonzalez-Lima, F.
关键词：
肌萎缩性侧索硬化症（ALS）是一种无法治愈的进行性麻痹性运动神经元疾病，治疗方案有限。自转基因SOD1G93A小鼠创建以来，已成为筛选ALS治疗方法的基准临床前模型。令人惊讶的是，尽管生理、解剖、超微结构和生化证据表明早期运动系统功能障碍，但在症状前SOD1G93A小鼠中检测运动功能障碍已被证明是困难的。作为常规强制运动测试的替代方法，我们研究了症状前行为自由的先天性B6的运动功能缺陷的进展。SOD1G93A老鼠。我们发现运动表现缺陷在明显临床症状出现前几周（出生后第45天）就开始了。更重要的是，一旦表现出运动能力缺陷，它们就会随着疾病的进展而持续存在。此外，肌肉周长的两项物理测量显示进行性后肢肌肉萎缩，在个体症状前小鼠中预测基因型的准确率为80%。总之，这些数据表明肌肉周长是后肢肌肉去神经支配的可靠和间接测量，也是先天性B6疾病发病的早期客观标志。SOD1G93A ALS小鼠。此外，我们提出了基于后肢肌肉周长的回归方程，用于预测未来使用B6的基因型。SOD1G93A老鼠。这些发现支持临床疾病发病的新的客观标准，并提供客观的措施，需要很少的专业知识。这些研究证明了一种经济有效的方法，可以更彻底地评估在疾病过程早期寻求破坏疾病机制的神经保护策略。据我们所知，这些发现是首次报道在任何ALS小鼠模型中与最早已知的运动功能障碍相一致的早期慢性运动表现和身体缺陷。
Amyotrophic lateral sclerosis (ALS) is an incurable progressive paralytic motor neuron disease with limited therapeutic options. Since their creation by, transgenic SOD1G93A mice have become the benchmark pre-clinical model for screening ALS therapies. Surprisingly, despite physiological, anatomical, ultrastructural and biochemical evidence of early motor system dysfunction it has proven difficult to detect motor performance deficits in pre-symptomatic SOD1G93A mice. As an alternative to conventional forced motor tests, we investigated the progression of motor performance deficits in freely behaving pre-symptomatic congenic B6.SOD1G93A mice. We found that motor performance deficits began several weeks prior to the onset of overt clinical symptoms (postnatal day 45). More importantly, once motor performance deficits manifested, they persisted in parallel with disease progression. In addition, two physical measures of muscle girth revealed progressive hindlimb muscle atrophy that predicted genotype in individual pre-symptomatic mice with 80% accuracy. Together, these data suggest that muscle girth is a reliable and indirect measure of hindlimb muscle denervation and an early, objective marker for disease onset in congenic B6.SOD1G93A ALS mice. Moreover, we present regression equations based on hindlimb muscle girth for predicting genotype in future studies using B6.SOD1G93A mice. These findings support new objective criteria for clinical disease onset and provide objective measures that require little expertise. These studies demonstrate a cost-effective approach for more thorough evaluation of neuroprotective strategies that seek to disrupt disease mechanisms early in the disease process. To our knowledge, these findings are the first to report early chronic motor performance and physical deficits that are coincident with the earliest known motor dysfunction in any ALS mouse model.
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