Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase

Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.运动神经元轴突的逆行性变性（dying-back degeneration）是与超氧化物歧化酶1（SOD1）突变相关的家族性肌萎缩侧索硬化症（FALS）的公认特征，但致病性SOD1的轴突自主效应仍未明确。FALS受累运动神经元的病理特征包括异常激酶激活、异常神经丝磷酸化以及快速轴突运输（FAT）缺陷，但上述各类致病事件之间的功能关联尚未阐明。对分离的鱿鱼轴浆开展的实验研究显示，与FALS相关的SOD1突变蛋白可通过涉及p38丝裂原活化蛋白激酶（p38 MAPK）通路的分子机制抑制快速轴突运输。突变型SOD1可在小鼠脊髓、神经母细胞瘤细胞及鱿鱼轴浆中激活神经元内的p38 MAPK；活化的p38 MAPK可磷酸化驱动蛋白-1，且该磷酸化事件会直接抑制驱动蛋白-1的功能。此外，囊泡运动实验还揭示了此前未被报道的、p38 MAPK对快速轴突运输的亚型特异性调控效应。p38通路的轴突自主激活代表了与FALS相关的SOD1蛋白的一种全新毒性功能获得机制，该机制与肌萎缩侧索硬化症典型的逆行性神经退行性变模式高度契合。