TY - JOUR
T1 - Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase
AU - Morfini, Gerardo A.
AU - Bosco, Daryl A.
AU - Brown, Hannah
AU - Gatto, Rodolfo
AU - Kaminska, Agnieszka
AU - Song, Yuyu
AU - Molla, Linda
AU - Baker, Lisa
AU - Marangoni, M. Natalia
AU - Berth, Sarah
AU - Tavassoli, Ehsan
AU - Bagnato, Carolina
AU - Tiwari, Ashutosh
AU - Hayward, Lawrence J.
AU - Pigino, Gustavo F.
AU - Watterson, D. Martin
AU - Huang, Chun Fang
AU - Banker, Gary
AU - Brown, Robert H.
AU - Brady, Scott T.
PY - 2013/6/12
Y1 - 2013/6/12
N2 - 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.
AB - 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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U2 - 10.1371/journal.pone.0065235
DO - 10.1371/journal.pone.0065235
M3 - Article
C2 - 23776455
AN - SCOPUS:84878900746
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 6
M1 - e65235
ER -