title: 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.
authors.affiliation: Depart of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, United States of America. gmorfini@uic.edu
authors.forename: Gerardo A
authors.initials: GA
authors.lastname: Morfini
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Bosco
authors.forename: Hannah
authors.initials: H
authors.lastname: Brown
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gatto
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kaminska
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Song
authors.forename: Linda
authors.initials: L
authors.lastname: Molla
authors.forename: Lisa
authors.initials: L
authors.lastname: Baker
authors.forename: M Natalia
authors.initials: MN
authors.lastname: Marangoni
authors.forename: Sarah
authors.initials: S
authors.lastname: Berth
authors.forename: Ehsan
authors.initials: E
authors.lastname: Tavassoli
authors.forename: Carolina
authors.initials: C
authors.lastname: Bagnato
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tiwari
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Hayward
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Pigino
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Huang
authors.forename: Gary
authors.initials: G
authors.lastname: Banker
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Scott T
authors.initials: ST
authors.lastname: Brady
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D049832:Decapodiformes; D007150:Immunohistochemistry; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology*; D010766:Phosphorylation; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D000072105:Superoxide Dismutase-1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048051:p38 Mitogen-Activated Protein Kinases; D016547:Kinesins