Delayed Disease Onset and Extended Survival in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis after Suppression of Mutant SOD1 in the Motor Cortex
Delayed Disease Onset and Extended Survival in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis after Suppression of Mutant SOD1 in the Motor Cortex
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DOI：
10.1523/jneurosci.2037-14.2014
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发表时间：
2014-11-19
影响因子：
5.3
通讯作者：
Svendsen, Clive N.
中科院分区：
文献类型：
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作者：
Thomsen, Gretchen M.;Gowing, Genevieve;Svendsen, Clive N.
散发性肌萎缩侧索硬化症(ALS)是一种病因不明的致命性疾病，以运动神经元进行性丧失为特征，通常在发病3-5年内导致瘫痪和死亡。最近，在理解遗传性肌萎缩侧索硬化症方面取得了显著进展，其中明确的突变被认为是导致疾病的原因。其中超氧化物歧化酶-1(SOD1)突变过度表达的啮齿动物模型概括了患者ALS的特征迹象。在FAL小鼠模型中，早期的解剖学变化见于神经肌肉接头(NMJ)和下运动神经元，选择性减少脊髓和肌肉中的有毒突变体SOD1具有有益的效果。因此，ALS的大部分研究都集中在脊髓运动神经元和NMJ方面。在SOD(G93A)大鼠ALS模型中，脊髓运动神经元的丢失发生在症状前和腹根轴突变性和NMJ失神经之前。虽然皮质脊髓运动神经元直到疾病终点才发生明显的细胞死亡，但我们想要确定上运动神经元是否仍然在疾病进展中发挥关键作用。令人惊讶的是，通过靶向传递AAV9-SOD1-shRNA，仅在症状前SOD1(G93A)大鼠的运动皮质中击倒突变的SOD1，显著延迟了疾病的发病，延长了寿命，提高了脊髓运动神经元的存活率，并维持了NMJ。这一数据表明，在ALS的动物模型中，上运动神经元存在早期功能障碍，因此在ALS的动物模型中，可能还有这种疾病的患者中，上运动神经元起着重要作用。
Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death typically within 3-5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients. Early anatomical changes in mouse models of fALS are seen in the neuromuscular junctions (NMJs) and lower motor neurons, and selective reduction of toxic mutant SOD1 in the spinal cord and muscle of these models has beneficial effects. Therefore, much of ALS research has focused on spinal motor neuron and NMJ aspects of the disease. Here we show that, in the SOD1(G93A) rat model of ALS, spinal motor neuron loss occurs presymptomatically and before degeneration of ventral root axons and denervation of NMJs. Although overt cell death of corticospinal motor neurons does not occur until disease endpoint, we wanted to establish whether the upper motor neuron might still play a critical role in disease progression. Surprisingly, the knockdown of mutant SOD1 in only the motor cortex of presymptomatic SOD1(G93A) rats through targeted delivery of AAV9-SOD1-shRNA resulted in a significant delay of disease onset, expansion of lifespan, enhanced survival of spinal motor neurons, and maintenance of NMJs. This datum suggests an early dysfunction and thus an important role of the upper motor neuron in this animal model of ALS and perhaps patients with the disease.