Age-dependent degeneration of an identified adult leg motor neuron in a Drosophila SOD1 model of ALS.
Age-dependent degeneration of an identified adult leg motor neuron in a Drosophila SOD1 model of ALS.
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DOI：
10.1242/bio.049692
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发表时间：
2020-10-21
期刊：
影响因子：
2.4
通讯作者：
Stilwell G
中科院分区：
文献类型：
--
作者：
Agudelo A;St Amand V;Grissom L;Lafond D;Achilli T;Sahin A;Reenan R;Stilwell G
超氧化物歧化酶1（SOD 1）突变导致人类家族性肌萎缩侧索硬化症（ALS）。ALS是一种神经退行性疾病，其特征在于进行性运动神经元损失，导致受影响个体的瘫痪和不可避免的死亡。使用基因替换策略引入疾病突变的orthopathy果蝇sod 1（dsod 1）基因，在这里，我们的特点是在神经肌肉接头使用寿命较长的dsod 1突变成人的变化。纯合子dsod 1H 71 Y/H71 Y或dsod 1 null/null果蝇表现出进行性行走缺陷，伴第三后胸腿麻痹。在解剖的腿，我们评估了一个单一的运动神经元（MN-I2）支配的胫骨提肌的年龄依赖性变化。在成虫羽化，MN-I2的dsod 1H 71 Y/H71 Y或sod 1 null/null苍蝇的图案类似于野生型苍蝇，表明没有明显的发育缺陷。在羽化后10天的过程中，MN-I2显示出在突变体dsod 1成年人中树枝状化的总体减少，具有终扣肿胀和突触后标记物盘大（dlg）的损失。 此外，多聚泛素化蛋白的增加与MN-I2变化的时间和程度相关。由于在dsod 1H 71 Y或dsod 1 null等位基因纯合子的果蝇之间观察到相似的表型，我们得出结论，这些NMJ变化主要与SOD功能丧失有关。这些研究共同表征了与ALS果蝇模型中轴突回缩相关的年龄相关的形态学和分子变化，这些变化概括了人类疾病的一个重要方面。总结：ALS的果蝇基因置换模型表现出神经肌肉接头的年龄依赖性拆除。
Mutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS) in humans. ALS is a neurodegenerative disease characterized by progressive motor neuron loss leading to paralysis and inevitable death in affected individuals. Using a gene replacement strategy to introduce disease mutations into the orthologous Drosophila sod1 (dsod1) gene, here, we characterize changes at the neuromuscular junction using longer-lived dsod1 mutant adults. Homozygous dsod1H71Y/H71Y or dsod1null/null flies display progressive walking defects with paralysis of the third metathoracic leg. In dissected legs, we assessed age-dependent changes in a single identified motor neuron (MN-I2) innervating the tibia levitator muscle. At adult eclosion, MN-I2 of dsod1H71Y/H71Y or sod1null/null flies is patterned similar to wild-type flies indicating no readily apparent developmental defects. Over the course of 10 days post-eclosion, MN-I2 shows an overall reduction in arborization with bouton swelling and loss of the post-synaptic marker discs-large (dlg) in mutant dsod1 adults. In addition, increases in polyubiquitinated proteins correlate with the timing and extent of MN-I2 changes. Because similar phenotypes are observed between flies homozygous for either dsod1H71Y or dsod1null alleles, we conclude these NMJ changes are mainly associated with sod loss-of-function. Together these studies characterize age-related morphological and molecular changes associated with axonal retraction in a Drosophila model of ALS that recapitulate an important aspect of the human disease. Summary: A Drosophila gene-replacement model of ALS exhibits age-dependent dismantling of the neuromuscular junction.