Mohajeri M H, Figlewicz D A, Bohn M C
Department of Neurobiology and Anatomy, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Exp Neurol. 1998 Apr;150(2):329-36. doi: 10.1006/exnr.1998.6758.
Mutations in the superoxide dismutase gene 1 (SOD-1) are found in patients with familial amyotrophic lateral sclerosis (FALS). Overexpression of a mutated human SOD-1 gene in mice results in neurodegenerative disease as result of motoneuron loss in lumbar spinal cord (10). Using this mouse model of FALS, we have established a quantitative assay utilizing the retrograde tracer Fluorogold (FG) to determine the number of motoneurons innervating one skeletal muscle in mice with ongoing disease. In adult wild-type mice, the number of alpha motoneurons retrogradely labeled by an injection of FG into medial gastrocnemius muscle is 50 +/- 7 and this number remains constant from 7 to 18 weeks of age. In mutant mice, the number of alpha motoneurons retrogradely labeled by FG is the same as in wild-type mice at 7 and 9 weeks, but then declines to 36% of that in normal mice at 18 weeks. This decline also correlates positively to severity of motor impairments in these mice as assessed by the hindlimb splay test. In contrast, the number of FG-labeled gamma motoneurons remains relatively unchanged in both wild-type and mutant mice up to 18 weeks. At 18 weeks of age, this apparent alpha motoneuron denervation is paralleled by an average of 55% reduction of MG-muscle mass and 40% weaker performance in the hindlimb splay test. These data suggest that alpha motoneurons are the most vulnerable neuronal subtype in this mouse model of ALS and it is primarily their loss that leads to functional motor deficits. This quantitative bioassay also will be valuable for evaluating novel therapeutics for ALS.
在家族性肌萎缩侧索硬化症（FALS）患者中发现超氧化物歧化酶基因1（SOD-1）发生突变。在小鼠中过表达突变的人类SOD-1基因会导致神经退行性疾病，这是由于腰脊髓运动神经元丧失所致（10）。利用这种FALS小鼠模型，我们建立了一种定量检测方法，利用逆行示踪剂荧光金（FG）来确定患有进行性疾病的小鼠中支配一块骨骼肌的运动神经元数量。在成年野生型小鼠中，通过向腓肠肌内侧注射FG逆行标记的α运动神经元数量为50±7，且该数量在7至18周龄时保持恒定。在突变小鼠中，7周和9周时FG逆行标记的α运动神经元数量与野生型小鼠相同，但在18周时降至正常小鼠的36%。这种下降也与通过后肢伸展试验评估的这些小鼠运动障碍的严重程度呈正相关。相比之下，在野生型和突变型小鼠中，直至18周龄，FG标记的γ运动神经元数量相对保持不变。在18周龄时，这种明显的α运动神经元去神经支配伴随着腓肠肌平均肌肉质量减少55%以及后肢伸展试验中表现减弱40%。这些数据表明，在这种ALS小鼠模型中，α运动神经元是最易受损的神经元亚型，主要是它们的丧失导致了功能性运动缺陷。这种定量生物检测方法对于评估ALS的新型治疗方法也将具有重要价值。
