Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease
Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease
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DOI：
10.1016/s0960-9822(03)00206-9
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发表时间：
2003-04-15
期刊：
影响因子：
9.2
通讯作者：
Kato, AC
中科院分区：
文献类型：
--
作者：
Ferri, A;Sanes, JR;Kato, AC
细胞凋亡是运动神经元疾病的一个标志，比如肌萎缩侧索硬化症（ALS）和脊髓性肌萎缩症（SMA）[1]。在一种广泛使用的运动神经元疾病小鼠模型（进行性运动神经元病，简称pmn）[2 - 4]中，抗凋亡的bcl - 2基因的转基因表达[5]或者用胶质细胞源性神经营养因子治疗[6]可阻止运动神经元胞体的凋亡；然而，它们无法影响动物的寿命。本研究的目的是确定pmn表型是否可通过一种抑制轴突退变的基因来挽救。基于此原因，将pmn小鼠与携带显性Wlds（“沃勒变性缓慢”）突变的小鼠杂交，该突变可减缓轴突退变和突触丢失[7 - 9]。我们在此表明，Wlds基因产物可减轻症状、延长寿命、防止轴突退变、挽救运动神经元的数量和大小，并延缓pmn/pmn小鼠的逆行运输缺陷。这些结果为运动神经元疾病提示了新的致病机制和治疗途径。
Apoptosis is a hallmark of motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) [1]. In a widely used mouse model of motoneuron disease (progressive motor neuronopathy or pmn) [2-4], transgenic expression of the antiapoptotic bcl-2 gene [5] or treatment with glial cell-derived neurotrophic factor [6] prevents the apoptosis of the motoneuron soma; however, they were unable to affect the life span of the animals. The goal of the present work was to determine whether the pmn phenotype could be rescued by means of a gene that inhibits axon degeneration. For this reason, the pmn mice were crossed with mice bearing the dominant Wlds ("slow Wallerian degeneration") mutation, which slows axon degeneration and synapse loss [7-9]. We show here that the Wlds gene product attenuates symptoms, extends life span, prevents axon degeneration, rescues motoneuron number and size, and delays retrograde transport deficits in pmn/pmn mice. These results suggest new pathogenic mechanisms and therapeutic avenues for motoneuron diseases.