Axonal transport defects are a common phenotype in Drosophila models of ALS.
Axonal transport defects are a common phenotype in Drosophila models of ALS.
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DOI：
10.1093/hmg/ddw105
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发表时间：
2016-06-15
影响因子：
3.5
通讯作者：
Whitworth AJ
中科院分区：
文献类型：
--
作者：
Baldwin KR;Godena VK;Hewitt VL;Whitworth AJ
肌萎缩侧索硬化症(ALS)的特征是运动神经元变性，导致运动功能的灾难性丧失。由于对病理生物学的机械性理解不佳，目前的治疗方法严重受限。大量基因的突变现已与肌萎缩侧索硬化症有关，包括SOD1、TARDBP(TDP-43)、FUS和C9orf72。对这些基因及其致病突变的功能分析为深入了解潜在的疾病机制提供了很好的见解。轴突运输缺陷被认为是运动神经选择性易损性的关键因素，因为它们非常长，而且有证据表明ALS是作为远端轴索病发生的。轴突运输被认为是细胞丢失和临床症状之前的早期致病事件，因此代表了治疗靶向的上游机制。一些研究已经开始描述一些致病突变对轴突运输的影响，但需要对一系列模型和货物进行广泛的调查。在这里，我们评估了ALS的多个果蝇模型中不同货物的轴突运输。我们发现轴突运输缺陷在所有被测试的模型中都是常见的，尽管它们通常在线粒体和囊泡之间表现出不同的效应。运动缺陷在所有模型中也很常见，通常随着年龄的增长而恶化，尽管令人惊讶的是，轴突运输缺陷的严重程度与运动能力之间没有明显的相关性。这些结果进一步支持轴突运输缺陷是ALS模型中的一个共同因素，可能有助于ALS的发病过程。
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons resulting in a catastrophic loss of motor function. Current therapies are severely limited owing to a poor mechanistic understanding of the pathobiology. Mutations in a large number of genes have now been linked to ALS, including SOD1, TARDBP (TDP-43), FUS and C9orf72. Functional analyses of these genes and their pathogenic mutations have provided great insights into the underlying disease mechanisms. Defective axonal transport is hypothesized to be a key factor in the selective vulnerability of motor nerves due to their extraordinary length and evidence that ALS occurs as a distal axonopathy. Axonal transport is seen as an early pathogenic event that precedes cell loss and clinical symptoms and so represents an upstream mechanism for therapeutic targeting. Studies have begun to describe the impact of a few pathogenic mutations on axonal transport but a broad survey across a range of models and cargos is warranted. Here, we assessed the axonal transport of different cargos in multiple Drosophila models of ALS. We found that axonal transport defects are common across all models tested, although they often showed a differential effect between mitochondria and vesicle cargos. Motor deficits were also common across the models and generally worsened with age, though surprisingly there was not a clear correlation between the severity of axonal transport defects and motor ability. These results further support defects in axonal transport as a common factor in models of ALS that may contribute to the pathogenic process.