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

GERARDO A. MORFINI; DARYL A. BOSCO; HANNAH BROWN; RODOLFO GATTO; AGNIESZKA KAMINSKA; YUYU SONG; LINDA MOLLA; LISA BAKER; M. NATALIA MARANGONI; SARAH BERTH; EHSAN TAVASSOLI; CAROLINA BAGNATO; ASHUTOSH TIWARI; LAWRENCE J. HAYWARD; GUSTAVO F. PIGINO; D. MARTIN WATTERSON; CHUN-FANG HUANG; GARY BANKER; ROBERT H. BROWN JR; SCOTT T. BRADY

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2013

1932-6203

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 SOD1remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrantneurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among thesepathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutantpolypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinasephosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealedpreviously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathwayrepresents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern ofneurodegeneration characteristic of ALS.