Biomolecular Sensors and Center for Integrated Protein Sciences (Munich) at the Institute of Neuroscience, Technische Universität München, 80802 Munich, Germany.
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4296-301. doi: 10.1073/pnas.1200658109. Epub 2012 Feb 27.
Axonal transport deficits have been reported in many neurodegenerative conditions and are widely assumed to be an immediate causative step of axon and synapse loss. By imaging changes in axonal morphology and organelle transport over time in several animal models of amyotrophic lateral sclerosis (ALS), we now find that deficits in axonal transport of organelles (mitochondria, endosomes) and axon degeneration can evolve independently. This conclusion rests on the following results: (i) Axons can survive despite long-lasting transport deficits: In the SOD(G93A) model of ALS, transport deficits are detected soon after birth, months before the onset of axon degeneration. (ii) Transport deficits are not necessary for axon degeneration: In the SOD(G85R) model of ALS, motor axons degenerate, but transport is unaffected. (iii) Axon transport deficits are not sufficient to cause immediate degeneration: In mice that overexpress wild-type superoxide dismutase-1 (SOD(WT)), axons show chronic transport deficits, but survive. These data suggest that disturbances of organelle transport are not a necessary step in the emergence of motor neuron degeneration.
轴突运输缺陷在许多神经退行性疾病中都有报道，并且广泛认为是轴突和突触丧失的直接原因。通过对几种肌萎缩侧索硬化症（ALS）动物模型中轴突形态和细胞器运输随时间的变化进行成像，我们现在发现细胞器（线粒体、内体）和轴突退化的轴突运输缺陷可以独立进化。这一结论基于以下结果：（i）尽管存在长期的运输缺陷，轴突仍能存活：在 ALS 的 SOD(G93A)模型中，出生后不久就检测到运输缺陷，在轴突退化之前的几个月。（ii）运输缺陷不是轴突退化所必需的：在 ALS 的 SOD(G85R)模型中，运动轴突退化，但运输不受影响。（iii）轴突运输缺陷不足以导致立即退化：在过表达野生型超氧化物歧化酶-1 (SOD(WT))的小鼠中，轴突显示出慢性运输缺陷，但仍能存活。这些数据表明，细胞器运输的紊乱不是运动神经元退化出现的必要步骤。
