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Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase.

ABSTRACT: 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.

SUBMITTER: Morfini GA

PROVIDER: S-EPMC3680447 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase.

Morfini Gerardo A GA Bosco Daryl A DA Brown Hannah H Gatto Rodolfo R Kaminska Agnieszka A Song Yuyu Y Molla Linda L Baker Lisa L Marangoni M Natalia MN Berth Sarah S Tavassoli Ehsan E Bagnato Carolina C Tiwari Ashutosh A Hayward Lawrence J LJ Pigino Gustavo F GF Watterson D Martin DM Huang Chun-Fang CF Banker Gary G Brown Robert H RH Brady Scott T ST

PloS one 20130612 6

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. Experi ...[more]

PMID: 23776455

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Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase.

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Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase.

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