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Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. 2013
Gerardo A Morfini, and
Daryl A Bosco, and
Hannah Brown, and
Rodolfo Gatto, and
Agnieszka Kaminska, and
Yuyu Song, and
Linda Molla, and
Lisa Baker, and
M Natalia Marangoni, and
Sarah Berth, and
Ehsan Tavassoli, and
Carolina Bagnato, and
Ashutosh Tiwari, and
Lawrence J Hayward, and
Gustavo F Pigino, and
D Martin Watterson, and
Chun-Fang Huang, and
Gary Banker, and
Robert H Brown, and
Scott T Brady
Depart of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, United States of America. gmorfini@uic.edu
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.
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