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dc.contributor.authorMorfini, Gerardo A.  Concept link
dc.contributor.authorBosco, Daryl A.  Concept link
dc.contributor.authorBrown, Hannah  Concept link
dc.contributor.authorGatto, Rodolfo  Concept link
dc.contributor.authorKaminska, Agnieszka  Concept link
dc.contributor.authorSong, Yuyu  Concept link
dc.contributor.authorMolla, Linda  Concept link
dc.contributor.authorBaker, Lisa  Concept link
dc.contributor.authorMarangoni, M. Natalia  Concept link
dc.contributor.authorBerth, Sarah  Concept link
dc.contributor.authorTavassoli, Ehsan  Concept link
dc.contributor.authorBagnato, Carolina  Concept link
dc.contributor.authorTiwari, Ashutosh  Concept link
dc.contributor.authorHayward, Lawrence J.  Concept link
dc.contributor.authorPigino, Gustavo F.  Concept link
dc.contributor.authorWatterson, D. Martin  Concept link
dc.contributor.authorHuang, Chun-Fang  Concept link
dc.contributor.authorBanker, Gary  Concept link
dc.contributor.authorBrown, Robert H.  Concept link
dc.contributor.authorBrady, Scott T.  Concept link
dc.date.accessioned2013-07-29T15:56:02Z
dc.date.available2013-07-29T15:56:02Z
dc.date.issued2013-06-12
dc.identifier.citationPLoS ONE 8 (2013): e65235en_US
dc.identifier.urihttps://hdl.handle.net/1912/6122
dc.description© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 8 (2013): e65235, doi:10.1371/journal.pone.0065235.en_US
dc.description.abstractDying-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.en_US
dc.description.sponsorshipSupport was provided by 2007/2008 Marine Biological Laboratory summer fellowships and NIH (NS066942A) grants to GM; Howard Hughes Medical Institute-USE Grant #52006287 to Hunter College of CUNY (LM); Muscular Dystrophy Association (MDA) and NIH (R01NS44170) grants to LJH; MDA and NIH (NS23868, NS23320, NS41170) grants to STB; NIH grant MH066179 to GB; NIH grants R01AG031311 and R01NS055951 to DMW; NIH (U01NS05225, R01NS050557, 1RC1NS068391, 1RC2NS070342) grants to RHB; R01NS067206 to DAB; ALS Association grants to GM, AT, RHB, and STB; and ALS/CVS Therapy Alliance grants to RHB, GM, AT, LJH, and DAB. RHB and AT received support from the Angel Fund. RHB also received support from the DeBourgknecht Fund for ALS Research, P2ALS and Project ALS.en_US
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dc.language.isoen_USen_US
dc.publisherPublic Library of Sceinceen_US
dc.relation.urihttps://doi.org/10.1371/journal.pone.0065235
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.titleInhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinaseen_US
dc.typeArticleen_US
dc.identifier.doi10.1371/journal.pone.0065235


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Attribution 3.0 United States
Except where otherwise noted, this item's license is described as Attribution 3.0 United States