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The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS.
- Source :
-
PloS one [PLoS One] 2016 Oct 03; Vol. 11 (10), pp. e0162307. Date of Electronic Publication: 2016 Oct 03 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- 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.<br />Competing Interests: Patents protecting this work were filed by McGill University (MF, NC, and HUS, inventors).
- Subjects :
- Amyotrophic Lateral Sclerosis drug therapy
Animals
Antibodies, Monoclonal immunology
Astrocytes physiology
Disease Models, Animal
Humans
Mice
MicroRNAs physiology
Motor Neurons drug effects
Motor Neurons physiology
Nerve Growth Factors physiology
Neuroprotective Agents therapeutic use
Protein Conformation
Protein Isoforms physiology
Rats
Receptor, trkC drug effects
Receptor, trkC immunology
Tumor Necrosis Factor-alpha physiology
Amyotrophic Lateral Sclerosis physiopathology
Receptor, trkC physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 27695040
- Full Text :
- https://doi.org/10.1371/journal.pone.0162307