Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons. We have previously shown that autophagosome-like vesicular structures are progressively accumulated in the spinal axons of an ALS mouse model, overexpressing human Cu/Zn superoxide dismutase (SOD1) mutant, prior to the onset of motor symptoms. This suggests that axonal transport perturbation can be an early sign of neuronal dysfunction. However, the exact causal relationship between axonal transport deficits and neurodegeneration is not fully understood. To clarify whether axonal transport of organelles even in neurons at early developmental stages was affected by overexpression of mutant SOD1, we conducted a microfluidic device-based high-throughput quantitative analysis of the axonal transport of acidic vesicles and mitochondria in primary cultured cortical neurons established from SOD1^H46R transgenic mice. Compared to wild-type (WT), a significantly increased number of motile acidic vesicles, i.e., autophagosomes and/or late-endosomes, was observed in the axons of SOD1^H46R neurons. By contrast, mitochondria moving along the axons were significantly decreased in SOD1^H46R compared to WT. Since such phenotypes, where the axonal transport of these organelles is differently affected by mutant SOD1 expression, emerge before axonal degeneration, axonal transport deficits could dysregulate axon homeostasis, thereby ultimately accelerating neurodegeneration.

肌萎缩侧索硬化症（ALS）是一种以运动神经元选择性丧失为特征的神经退行性疾病。我们之前已经表明，自噬体样囊泡结构在 ALS 小鼠模型的脊髓轴突中逐渐积累，在运动症状发作之前过度表达人类铜/锌超氧化物歧化酶 (SOD1) 突变体。这表明轴突运输扰动可能是神经元功能障碍的早期迹象。然而，轴突运输缺陷与神经退行性变之间的确切因果关系尚不完全清楚。为了阐明即使在早期发育阶段的神经元中细胞器的轴突运输是否受到突变 SOD1 过表达的影响，^H46R转基因小鼠。与野生型 (WT) 相比，在 SOD1 ^H46R神经元的轴突中观察到运动酸性囊泡的数量显着增加，即自噬体和/或晚期内体。相比之下，与 WT 相比，SOD1 ^{H46R 中}沿轴突移动的线粒体显着减少。由于这些细胞器的轴突运输受突变 SOD1 表达的不同影响的这种表型出现在轴突变性之前，因此轴突运输缺陷可能会失调轴突稳态，从而最终加速神经变性。