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dc.contributor.authorBrahimi, Fouad
dc.contributor.authorMaira, Mario
dc.contributor.authorBarcelona, Pablo F
dc.contributor.authorGalan, Alba
dc.contributor.authorAboulkassim, Tahar
dc.contributor.authorTeske, Katrina
dc.contributor.authorRogers, Mary-Louise
dc.contributor.authorBertram, Lisa
dc.contributor.authorWang, Jing
dc.contributor.authorYousefi, Masoud
dc.contributor.authorRush, Robert
dc.contributor.authorFabian, Marc
dc.contributor.authorCashman, Neil
dc.contributor.authorSaragovi, H Uri
dc.date.accessioned2016-11-29T05:26:16Z
dc.date.available2016-11-29T05:26:16Z
dc.date.issued2016-10-03
dc.identifier.citationBrahimi F, Maira M, Barcelona PF, Galan A, Aboulkassim T, Teske K, et al. (2016) The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS. PLoS ONE 11(10): e0162307. doi:10.1371/journal.pone.0162307en
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/2328/36783
dc.descriptionThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.description.abstractFull length TrkC (TrkC-FL) is a receptor tyrosine kinase whose mRNA can be spliced to a truncated TrkC.T1 isoform lacking the kinase domain. Neurotrophin-3 (NT-3) activates TrkC-FL to maintain motor neuron health and function and TrkC.T1 to produce neurotoxic TNF-α; hence resulting in opposing pathways. In mouse and human ALS spinal cord, the reduction of miR-128 that destabilizes TrkC.T1 mRNA results in up-regulated TrkC.T1 and TNF-α in astrocytes. We exploited conformational differences to develop an agonistic mAb 2B7 that selectively activates TrkC-FL, to circumvent TrkC.T1 activation. In mouse ALS, 2B7 activates spinal cord TrkC-FL signals, improves spinal cord motor neuron phenotype and function, and significantly prolongs life-span. Our results elucidate biological paradoxes of receptor isoforms and their role in disease progression, validate the concept of selectively targeting conformational epitopes in naturally occurring isoforms, and may guide the development of pro-neuroprotective (TrkC-FL) and anti-neurotoxic (TrkC.T1) therapeutic strategies.en
dc.language.isoen
dc.publisherPublic Library of Scienceen
dc.rights© 2016 Brahimi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectAmyotrophic lateral sclerosis (ALS)en
dc.subjecttyrosine kinaseen
dc.subjectTrkCen
dc.subjectmotor neuron health and functionen
dc.titleThe Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALSen
dc.typeArticleen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0162307en
dc.rights.holderThe authorsen
local.contributor.authorOrcidLookupRogers, Mary-Louise: https://orcid.org/0000-0002-3482-8741en_US


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