The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS

Autores
Brahimi, Fouad; Maira, Mario; Barcelona, Pablo Federico; Galan, Alba; Aboulkassim, Tahar; Teske, Katrina; Rogers, Mary Louise; Bertram, Lisa; Wang, Jing; Yousefi, Masoud; Rush, Robert; Fabian, Marc; Cashman, Neil; Saragovi, H. Uri
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Full 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.
Fil: Brahimi, Fouad. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Maira, Mario. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Galan, Alba. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Aboulkassim, Tahar. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Teske, Katrina. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Rogers, Mary Louise. Flinders University, Department Of Human Physiology; Australia
Fil: Bertram, Lisa. University of British Columbia; Canadá
Fil: Wang, Jing. University of British Columbia; Canadá
Fil: Yousefi, Masoud. University of British Columbia; Canadá
Fil: Rush, Robert. Flinders University, Department Of Human Physiology; Australia
Fil: Fabian, Marc. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Cashman, Neil. University of British Columbia; Canadá
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
Materia
FULL LENGHT TrkC
NEUROTROPHIM-3 (NT-3)
AMIOTROPHIC LATERAL SCLEROSIS
SPINAL CORD
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/46608
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/46608
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALSBrahimi, FouadMaira, MarioBarcelona, Pablo FedericoGalan, AlbaAboulkassim, TaharTeske, KatrinaRogers, Mary LouiseBertram, LisaWang, JingYousefi, MasoudRush, RobertFabian, MarcCashman, NeilSaragovi, H. UriFULL LENGHT TrkCNEUROTROPHIM-3 (NT-3)AMIOTROPHIC LATERAL SCLEROSISSPINAL CORDhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Full 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.Fil: Brahimi, Fouad. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Maira, Mario. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Galan, Alba. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Aboulkassim, Tahar. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Teske, Katrina. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Rogers, Mary Louise. Flinders University, Department Of Human Physiology; AustraliaFil: Bertram, Lisa. University of British Columbia; CanadáFil: Wang, Jing. University of British Columbia; CanadáFil: Yousefi, Masoud. University of British Columbia; CanadáFil: Rush, Robert. Flinders University, Department Of Human Physiology; AustraliaFil: Fabian, Marc. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Cashman, Neil. University of British Columbia; CanadáFil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; CanadáPublic Library of Science2016-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/46608Brahimi, Fouad; Maira, Mario; Barcelona, Pablo Federico; Galan, Alba; Aboulkassim, Tahar; et al.; The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS; Public Library of Science; Plos One; 11; 10; 10-20161932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://bit.ly/2spwZ53info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0162307info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:10:29Zoai:ri.conicet.gov.ar:11336/46608instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:10:29.495CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS
title The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS
spellingShingle The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS
Brahimi, Fouad
FULL LENGHT TrkC
NEUROTROPHIM-3 (NT-3)
AMIOTROPHIC LATERAL SCLEROSIS
SPINAL CORD
title_short The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS
title_full The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS
title_fullStr The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS
title_full_unstemmed The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS
title_sort The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS
dc.creator.none.fl_str_mv Brahimi, Fouad
Maira, Mario
Barcelona, Pablo Federico
Galan, Alba
Aboulkassim, Tahar
Teske, Katrina
Rogers, Mary Louise
Bertram, Lisa
Wang, Jing
Yousefi, Masoud
Rush, Robert
Fabian, Marc
Cashman, Neil
Saragovi, H. Uri
author Brahimi, Fouad
author_facet Brahimi, Fouad
Maira, Mario
Barcelona, Pablo Federico
Galan, Alba
Aboulkassim, Tahar
Teske, Katrina
Rogers, Mary Louise
Bertram, Lisa
Wang, Jing
Yousefi, Masoud
Rush, Robert
Fabian, Marc
Cashman, Neil
Saragovi, H. Uri
author_role author
author2 Maira, Mario
Barcelona, Pablo Federico
Galan, Alba
Aboulkassim, Tahar
Teske, Katrina
Rogers, Mary Louise
Bertram, Lisa
Wang, Jing
Yousefi, Masoud
Rush, Robert
Fabian, Marc
Cashman, Neil
Saragovi, H. Uri
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv FULL LENGHT TrkC
NEUROTROPHIM-3 (NT-3)
AMIOTROPHIC LATERAL SCLEROSIS
SPINAL CORD
topic FULL LENGHT TrkC
NEUROTROPHIM-3 (NT-3)
AMIOTROPHIC LATERAL SCLEROSIS
SPINAL CORD
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Full 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.
Fil: Brahimi, Fouad. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Maira, Mario. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Galan, Alba. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Aboulkassim, Tahar. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Teske, Katrina. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Rogers, Mary Louise. Flinders University, Department Of Human Physiology; Australia
Fil: Bertram, Lisa. University of British Columbia; Canadá
Fil: Wang, Jing. University of British Columbia; Canadá
Fil: Yousefi, Masoud. University of British Columbia; Canadá
Fil: Rush, Robert. Flinders University, Department Of Human Physiology; Australia
Fil: Fabian, Marc. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Cashman, Neil. University of British Columbia; Canadá
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
description Full 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.
publishDate 2016
dc.date.none.fl_str_mv 2016-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/46608
Brahimi, Fouad; Maira, Mario; Barcelona, Pablo Federico; Galan, Alba; Aboulkassim, Tahar; et al.; The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS; Public Library of Science; Plos One; 11; 10; 10-2016
1932-6203
CONICET Digital
CONICET
url http://hdl.handle.net/11336/46608
identifier_str_mv Brahimi, Fouad; Maira, Mario; Barcelona, Pablo Federico; Galan, Alba; Aboulkassim, Tahar; et al.; The paradoxical signals of two TrkC receptor isoforms supports a rationale for novel therapeutic strategies in ALS; Public Library of Science; Plos One; 11; 10; 10-2016
1932-6203
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://bit.ly/2spwZ53
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0162307
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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