Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila.
Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila.
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作者：
D. D. Hurd-D.;W. Saxton
先前的工作表明，编码果蝇微管运动亚单位驱动蛋白重链（Khc）的基因突变抑制神经元钠通道活性、动作电位和神经递质分泌。这些生理缺陷导致幼虫进行性远端麻痹。为了确定导致这些表型的细胞缺陷，幼虫神经进行了研究，通过光学和电子显微镜。Khc突变体的轴突沿其长度发展戏剧性的局灶性硬化沿着。轴突中充满了快速轴突运输的货物，包括囊泡，突触膜蛋白，线粒体和前溶酶体细胞器，但没有缓慢的轴突运输货物，如细胞骨架元素。Khc突变也损害了幼虫运动轴突终末的发育，导致营养不良的形态和突触终末数量的显着减少。这些观察结果表明，随着母体提供的野生型KHC的浓度降低，由驱动蛋白运输的轴突细胞器定期失速。这会导致细胞器堵塞，破坏逆行和顺行的快速轴突运输，导致动作电位缺陷，营养不良的终端，减少递质分泌和进行性远端瘫痪。这些表型平行的一些脊椎动物运动神经元疾病，包括肌萎缩侧索硬化症（ALS）的某些形式的病理，并表明，受损的快速轴突运输是这些疾病的关键因素。
Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal organelles transported by kinesin periodically stall. This causes organelle jams that disrupt retrograde as well as anterograde fast axonal transport, leading to defective action potentials, dystrophic terminals, reduced transmitter secretion and progressive distal paralysis. These phenotypes parallel the pathologies of some vertebrate motor neuron diseases, including some forms of amyotrophic lateral sclerosis (ALS), and suggest that impaired fast axonal transport is a key element in these diseases.