Department of Psychology, Institute for Neuroscience, University of Texas at Austin, 2701 Speedway, Austin, TX 78712, USA.
Neuroscience. 2009 Dec 15;164(3):975-85. doi: 10.1016/j.neuroscience.2009.08.031. Epub 2009 Aug 20.
Amyotrophic lateral sclerosis (ALS) is an incurable progressive paralytic motor neuron disease with limited therapeutic options. Since their creation by Gurney et al. (1994) [Science 264:1772-1775], transgenic superoxide dismutase-1 with glycine to alanine switch at codon 93 (SOD1(G93A)) 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 SOD1(G93A) mice. As an alternative to conventional forced motor tests, we investigated the progression of motor performance deficits in freely behaving pre-symptomatic congenic B6.SOD1(G93A) 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.SOD1(G93A) ALS mice. Moreover, we present regression equations based on hindlimb muscle girth for predicting genotype in future studies using B6.SOD1(G93A) 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.
肌萎缩侧索硬化症（ALS）是一种无法治愈的进行性瘫痪运动神经元疾病，治疗选择有限。自 Gurney 等人创建以来（1994 年）[Science 264:1772-1775]，具有甘氨酸到丙氨酸突变的超氧化物歧化酶 1（SOD1（G93A））转基因小鼠已成为筛选 ALS 治疗方法的基准临床前模型。令人惊讶的是，尽管有生理、解剖、超微结构和生化证据表明早期运动系统功能障碍，但在无症状 SOD1（G93A）小鼠中检测到运动表现缺陷仍然很困难。作为传统强制运动测试的替代方法，我们研究了自由行为无症状同基因 B6.SOD1（G93A）小鼠运动表现缺陷的进展。我们发现运动表现缺陷早在明显临床症状出现前几周就开始了（出生后第 45 天）。更重要的是，一旦运动表现缺陷表现出来，它们就会与疾病进展平行持续存在。此外，两个肌肉周长的物理测量显示进行性后肢肌肉萎缩，以 80%的准确率预测个体无症状前 SOD1（G93A）小鼠的基因型。这些数据共同表明，肌肉周长是后肢肌肉失神经支配的可靠且间接指标，也是同基因 B6.SOD1（G93A）ALS 小鼠疾病发作的早期客观标志物。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 B6.SOD1（G93A）小鼠研究中的基因型。这些发现支持了临床疾病发作的新客观标准，并提供了需要很少专业知识的客观指标。这些研究为更彻底地评估旨在早期破坏疾病机制的神经保护策略提供了一种具有成本效益的方法。据我们所知，这些发现是首次报告在任何 ALS 小鼠模型中与最早已知的运动功能障碍同时发生的早期慢性运动表现和身体缺陷。
