The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS.
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 pathw...
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2016-01-01
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doaj-9586ff7d786941bea985576cde95b1542020-11-25T00:44:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-011110e016230710.1371/journal.pone.0162307The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS.Fouad BrahimiMario MairaPablo F BarcelonaAlba GalanTahar AboulkassimKatrina TeskeMary-Louise RogersLisa BertramJing WangMasoud YousefiRobert RushMarc FabianNeil CashmanH Uri SaragoviFull 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.http://europepmc.org/articles/PMC5047590?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fouad Brahimi Mario Maira Pablo F Barcelona Alba Galan Tahar Aboulkassim Katrina Teske Mary-Louise Rogers Lisa Bertram Jing Wang Masoud Yousefi Robert Rush Marc Fabian Neil Cashman H Uri Saragovi |
spellingShingle |
Fouad Brahimi Mario Maira Pablo F Barcelona Alba Galan Tahar Aboulkassim Katrina Teske Mary-Louise Rogers Lisa Bertram Jing Wang Masoud Yousefi Robert Rush Marc Fabian Neil Cashman H Uri Saragovi The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS. PLoS ONE |
author_facet |
Fouad Brahimi Mario Maira Pablo F Barcelona Alba Galan Tahar Aboulkassim Katrina Teske Mary-Louise Rogers Lisa Bertram Jing Wang Masoud Yousefi Robert Rush Marc Fabian Neil Cashman H Uri Saragovi |
author_sort |
Fouad Brahimi |
title |
The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS. |
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 |
paradoxical signals of two trkc receptor isoforms supports a rationale for novel therapeutic strategies in als. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2016-01-01 |
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. |
url |
http://europepmc.org/articles/PMC5047590?pdf=render |
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