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 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.
Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.
Fouad
F
Brahimi
Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.
Mario
M
Maira
Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.
Pablo F
PF
Barcelona
Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.
Alba
A
Galan
Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.
Tahar
T
Aboulkassim
Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.
Katrina
K
Teske
Flinders University, Department of Human Physiology, Centre for Neuroscience, Adelaide, Australia.
Mary-Louise
ML
Rogers
University of British Columbia. Brain Research Centre, Vancouver, Canada.
Lisa
L
Bertram
University of British Columbia. Brain Research Centre, Vancouver, Canada.
Jing
J
Wang
University of British Columbia. Brain Research Centre, Vancouver, Canada.
Masoud
M
Yousefi
Flinders University, Department of Human Physiology, Centre for Neuroscience, Adelaide, Australia.
Robert
R
Rush
Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.|Department of Biochemistry. McGill University, Montréal, QC, Canada.
Marc
M
Fabian
University of British Columbia. Brain Research Centre, Vancouver, Canada.
Neil
N
Cashman
Lady Davis Institute-Jewish General Hospital, Translational Center, McGill University, Montréal, QC, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
H Uri
http://orcid.org/0000-0001-6884-8815
HU
Saragovi
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001253:Astrocytes / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011487:Protein Conformation; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D020812:Receptor, trkC / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000911:Antibodies, Monoclonal; C000618998:MIRN1288 microRNA, human; D035683:MicroRNAs; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; C518911:neurotropin 3, mouse; D020812:Receptor, trkC
Cell. 2004 Jul 23;118(2):141-3
15260984
Cell. 2010 Jun 25;141(7):1117-34
20602996
J Neurosci. 1988 Sep;8(9):3481-98
2845023
J Biol Chem. 2001 Aug 17;276(33):31023-9
11425862
J Neurobiol. 1999 May;39(2):323-36
10235685
Mol Cell Biol. 2015 Oct;35(19):3396-408
26217017
Neurobiol Dis. 2012 Nov;48(2):153-78
22525569
Neuron. 2006 Jul 6;51(1):21-8
16815329
Curr Alzheimer Res. 2009 Oct;6(5):419-23
19874265
Trends Pharmacol Sci. 2000 Mar;21(3):93-8
10689362
Trends Neurosci. 2012 Jul;35(7):431-40
22503537
Lancet. 2007 Jun 16;369(9578):2031-41
17574095
Exp Mol Med. 2009 Jul 31;41(7):487-500
19322031
Exp Neurol. 2013 Oct;248:170-82
23792206
Annu Rev Neurosci. 2003;26:299-330
12598680
J Neurosci. 1996 Feb 15;16(4):1308-16
8778282
PLoS One. 2012;7(6):e39946
22761934
Curr Opin Neurobiol. 2008 Jun;18(3):284-91
18725296
Neuron. 2003 Jul 3;39(1):57-68
12848932
Neuron. 2011 Jan 27;69(2):287-303
21262467
Exp Neurol. 2007 Sep;207 (1):52-63
17597610
Science. 1994 May 6;264(5160):772-4
8171331
Oncogene. 2003 Aug 28;22(36):5677-85
12944916
J Cell Biol. 2006 Apr 24;173(2):291-9
16636148
Neurochem Res. 1996 Jul;21(7):831-41
8873088
Nat Commun. 2014 Nov 11;5:5209
25385546
PLoS One. 2014 Jan 27;9(1):e87398
24475283
J Neurosci Res. 2004 Oct 15;78(2):193-9
15378612
J Neurol Sci. 2000 Nov 1;180(1-2):21-8
11090860
J Biol Chem. 2010 Dec 10;285(50):39392-400
20943663
Invest Ophthalmol Vis Sci. 1998 Jan;39(1):212-6
9430566
J Neurol Sci. 1998 Oct;160 Suppl 1:S97-105
9851658
Biochim Biophys Acta. 2010 Sep;1800(9):1018-26
20600627
J Neurosci. 2009 Apr 29;29(17):5536-45
19403821
Dev Neurobiol. 2010 Feb 15;70(3):150-64
19953569
Stem Cells Int. 2011;2011:207230
21716648
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3555-60
11248116
J Biol Chem. 2000 Apr 7;275(14):9946-56
10744669
Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6639-51
20574020
J Neurosci. 2010 Jul 21;30(29):9728-37
20660255
J Neurosci. 1997 Aug 15;17(16):6031-7
9236214
Peptides. 2009 Oct;30(10):1833-9
19647025
Acta Neuropathol. 1991;81(6):649-56
1715633
Neurobiol Dis. 2017 Jan;97(Pt B):139-155
27546056
Mol Pharmacol. 2011 Sep;80(3):498-508
21616921
Neurology. 2008 Nov 25;71(22):1770-5
19029516
Neurobiol Dis. 2009 Mar;33(3):473-81
19135533
ACS Chem Biol. 2009 Sep 18;4(9):769-81
19735123
Curr Pharm Des. 2002;8(24):2201-16
12369863
BMC Mol Biol. 2010 Dec 10;11:95
21143953
Eur J Neurosci. 2006 Sep;24(6):1575-80
17004921
J Neurosci. 2003 Feb 15;23(4):1424-31
12598631