Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS.
SOD1
ErbB4
TDP-43
immunohistochemistry
sporadic amyotrophic lateral sclerosis
Journal
Neuropathology : official journal of the Japanese Society of Neuropathology
ISSN: 1440-1789
Titre abrégé: Neuropathology
Pays: Australia
ID NLM: 9606526
Informations de publication
Date de publication:
Aug 2019
Aug 2019
Historique:
received:
30
12
2018
revised:
30
03
2019
accepted:
03
04
2019
pubmed:
28
5
2019
medline:
24
1
2020
entrez:
25
5
2019
Statut:
ppublish
Résumé
ErbB4 is the protein implicated in familial amyotrophic lateral sclerosis (ALS), designated as ALS19. ErbB4 is a receptor tyrosine kinase activated by its ligands, neuregulins (NRG), and plays an essential role in the function and viability of motor neurons. Mutations in the ALS19 gene lead to the reduced autophosphorylation capacity of the ErbB4 protein upon stimulation with NRG-1, suggesting that the disruption of the NRG-ErbB4 pathway causes motor neuron degeneration. We used immunohistochemistry to study ErbB4 in the spinal cord of patients with sporadic ALS (SALS) to test the hypothesis that ErbB4 may be involved in the pathogenesis of SALS. ErbB4 was specifically immunoreactive in the cytoplasm of motor neurons in the anterior horns of the spinal cord. In patients with SALS, some of the motor neurons lost immunoreactivity with ErbB4, with the proportion of motor neurons with a loss of immunoreactivity correlated with the severity of motor neuron loss. The subcellular localization was altered, demonstrating nucleolar or nuclear localization, threads/dots and spheroids. The ectopic glial immunoreactivity was observed, mainly in the oligodendrocytes of the lateral columns and anterior horns. The reduction in the ErbB4 immunoreactivity was significantly correlated with the cytoplasmic mislocalization of transactivation response DNA-binding protein 43 kDa (TDP-43) in the motor neurons. No alteration in immunoreactivity was observed in the motor neurons of mice carrying atransgene for mutant form of the superoxide dismutase 1 gene (SOD1). This study provided compelling evidence that ErbB4 is also involved in the pathophysiology of SALS, and that the disruption of the NRG-ErbB4 pathway may underlie the TDP-43-dependent motor neuron degeneration in ALS.
Identifiants
pubmed: 31124187
doi: 10.1111/neup.12558
pmc: PMC6852233
doi:
Substances chimiques
DNA-Binding Proteins
0
TARDBP protein, human
0
Sod1 protein, mouse
EC 1.15.1.1
Superoxide Dismutase-1
EC 1.15.1.1
ERBB4 protein, human
EC 2.7.10.1
Receptor, ErbB-4
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
268-278Subventions
Organisme : Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP
ID : 27-6
Organisme : Japan ALS Association
Organisme : Takeda Science Foundation
Informations de copyright
© 2019 The Authors. Neuropathology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Neuropathology.
Références
Brain Res. 2011 Aug 11;1406:65-73
pubmed: 21733494
J Neurosci. 2005 Jun 15;25(24):5757-62
pubmed: 15958742
Nature. 1995 Nov 23;378(6555):390-4
pubmed: 7477376
Neuron. 2001 May;30(2):399-410
pubmed: 11395002
Lab Invest. 1997 Apr;76(4):441-56
pubmed: 9111507
Front Cell Neurosci. 2013 Dec 17;7:258
pubmed: 24381541
Nature. 2014 Mar 13;507(7491):195-200
pubmed: 24598541
Dev Neurosci. 1996;18(5-6):492-8
pubmed: 8940623
J Histochem Cytochem. 2004 Oct;52(10):1299-311
pubmed: 15385576
PLoS One. 2009 Jul 03;4(7):e6128
pubmed: 19578540
Hum Mol Genet. 2015 May 1;24(9):2426-41
pubmed: 25575510
Proc Natl Acad Sci U S A. 2007 May 8;104(19):8131-6
pubmed: 17483467
Am J Hum Genet. 2013 Nov 7;93(5):900-5
pubmed: 24119685
Science. 2014 Sep 5;345(6201):1139-45
pubmed: 25081482
Acta Neuropathol Commun. 2016 Feb 18;4:15
pubmed: 26891847
Oncogene. 1999 Apr 22;18(16):2607-15
pubmed: 10353604
Neuron. 2000 Jan;25(1):79-91
pubmed: 10707974
Nat Rev Neurol. 2011 Oct 11;7(11):603-15
pubmed: 21989245
Sci Rep. 2017 Jan 09;7:40155
pubmed: 28065942
J Biol Chem. 2002 Feb 22;277(8):6318-23
pubmed: 11741961
PLoS One. 2008 Jun 04;3(6):e2310
pubmed: 18523588
Acta Neuropathol Commun. 2015 Sep 15;3:57
pubmed: 26374630
Nature. 1993 Dec 2;366(6454):473-5
pubmed: 7902537
FASEB J. 2014 Aug;28(8):3618-32
pubmed: 24803543
Nat Cell Biol. 2000 Feb;2(2):103-9
pubmed: 10655590
J Neuropathol Exp Neurol. 2003 Dec;62(12):1211-9
pubmed: 14692697
J Biol Chem. 1997 Oct 17;272(42):26761-8
pubmed: 9334263
Eur J Med Genet. 2014 Feb;57(2-3):103-12
pubmed: 24503148
Acta Neuropathol Commun. 2015 Jun 20;3:35
pubmed: 26091809
Neurodegener Dis. 2014;14(3):117-24
pubmed: 25115814
Cell. 2006 Oct 6;127(1):185-97
pubmed: 17018285
Nat Neurosci. 2012 Nov;15(11):1488-97
pubmed: 23023293
Behav Brain Res. 2004 Aug 12;153(1):159-70
pubmed: 15219717
Neuron. 2008 Aug 28;59(4):581-95
pubmed: 18760695
J Cell Biol. 2011 Dec 26;195(7):1171-84
pubmed: 22184199
J Neuropathol Exp Neurol. 2012 Feb;71(2):104-15
pubmed: 22249457
EMBO J. 2016 Nov 2;35(21):2350-2370
pubmed: 27621269
Growth Factors. 2008 Oct;26(5):263-74
pubmed: 18800267
Mol Biol Cell. 2010 Dec;21(23):4275-86
pubmed: 20943952
Exp Cell Res. 2003 Mar 10;284(1):66-77
pubmed: 12648466
J Neuropathol Exp Neurol. 1984 Sep;43(5):471-80
pubmed: 6540800
Ann Neurol. 2007 May;61(5):427-34
pubmed: 17469116
EMBO J. 1995 Dec 1;14(23):5842-8
pubmed: 8846777
Science. 2006 Oct 6;314(5796):130-3
pubmed: 17023659
J Neurocytol. 2003 Jun-Sep;32(5-8):649-64
pubmed: 15034258
Brain. 2013 Feb;136(Pt 2):471-82
pubmed: 23378219
J Biol Chem. 2011 Jan 14;286(2):1204-15
pubmed: 21051541