TY - JOUR
T1 - Decreased circulating ErbB4 ectodomain fragments as a read-out of impaired signaling function in amyotrophic lateral sclerosis
AU - Lopez-Font, Inmaculada
AU - Sogorb-Esteve, Aitana
AU - Javier-Torrent, Míriam
AU - Brinkmalm, Gunnar
AU - Herrando-Grabulosa, Mireia
AU - García-Lareu, Belen
AU - Turon-Sans, Janina
AU - Rojas-García, Ricardo
AU - Lleó, Alberto
AU - Saura, Carlos A.
AU - Zetterberg, Henrik
AU - Blennow, Kaj
AU - Bosch, Assumpció
AU - Navarro, Xavier
AU - Sáez-Valero, Javier
N1 - Copyright © 2019 Elsevier Inc. All rights reserved.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - © 2018 ErbB4 is a transmembrane receptor tyrosine kinase that binds to neuregulins to activate signaling. Proteolytic cleavage of ErbB4 results in release of soluble fragments of ErbB4 into the interstitial fluid. Disruption of the neuregulin-ErbB4 pathway has been suggested to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). This study assesses whether soluble proteolytic fragments of the ErbB4 ectodomain (ecto-ErbB4) can be detected in cerebrospinal fluid (CSF) and plasma, and if the levels are altered in ALS. Immunoprecipitation combined with mass spectrometry or western blotting analyses confirmed the presence of ecto-ErbB4 in human CSF. Several anti-ErbB4-reactive bands, including a 55 kDa fragment, were detected in CSF. The bands were generated in the presence of neuregulin-1 (Nrg1) and were absent in plasma from ErbB4 knockout mice. Ecto-ErbB4 levels were decreased in CSF from ALS patients (n = 20) and ALS with concomitant frontotemporal dementia patients (n = 10), compared to age-matched controls (n = 13). A similar decrease was found for the short ecto-ErbB4 fragments in plasma of the same subjects. Likewise, the 55-kDa ecto-ErbB4 fragments were decreased in the plasma of the two transgenic mouse models of ALS (SOD1G93A and TDP-43A315T). Intracellular ErbB4 fragments were decreased in the frontal cortex from SOD1G93A mice, indicating a reduction in Nrg-dependent induction of ErbB4 proteolytic processing, and suggesting impaired signaling. Accordingly, overexpression of Nrg1 induced by an adeno-associated viral vector increased the levels of the ecto-ErbB4 fragment in the SOD1G93A mice. We conclude that the determination of circulating ecto-ErbB4 fragments could be a tool to evaluate the impairment of the ErbB4 pathway and may be a useful biomarker in ALS.
AB - © 2018 ErbB4 is a transmembrane receptor tyrosine kinase that binds to neuregulins to activate signaling. Proteolytic cleavage of ErbB4 results in release of soluble fragments of ErbB4 into the interstitial fluid. Disruption of the neuregulin-ErbB4 pathway has been suggested to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). This study assesses whether soluble proteolytic fragments of the ErbB4 ectodomain (ecto-ErbB4) can be detected in cerebrospinal fluid (CSF) and plasma, and if the levels are altered in ALS. Immunoprecipitation combined with mass spectrometry or western blotting analyses confirmed the presence of ecto-ErbB4 in human CSF. Several anti-ErbB4-reactive bands, including a 55 kDa fragment, were detected in CSF. The bands were generated in the presence of neuregulin-1 (Nrg1) and were absent in plasma from ErbB4 knockout mice. Ecto-ErbB4 levels were decreased in CSF from ALS patients (n = 20) and ALS with concomitant frontotemporal dementia patients (n = 10), compared to age-matched controls (n = 13). A similar decrease was found for the short ecto-ErbB4 fragments in plasma of the same subjects. Likewise, the 55-kDa ecto-ErbB4 fragments were decreased in the plasma of the two transgenic mouse models of ALS (SOD1G93A and TDP-43A315T). Intracellular ErbB4 fragments were decreased in the frontal cortex from SOD1G93A mice, indicating a reduction in Nrg-dependent induction of ErbB4 proteolytic processing, and suggesting impaired signaling. Accordingly, overexpression of Nrg1 induced by an adeno-associated viral vector increased the levels of the ecto-ErbB4 fragment in the SOD1G93A mice. We conclude that the determination of circulating ecto-ErbB4 fragments could be a tool to evaluate the impairment of the ErbB4 pathway and may be a useful biomarker in ALS.
KW - ALS transgenic mouse
KW - Amyotrophic lateral sclerosis
KW - Biomarker
KW - Brain
KW - Cerebrospinal fluid
KW - ErbB4
KW - Plasma
KW - Receptor, ErbB-4/analysis
KW - Biomarkers/analysis
KW - Humans
KW - Middle Aged
KW - Male
KW - Mice, Transgenic
KW - Signal Transduction/physiology
KW - Animals
KW - Female
KW - Aged
KW - Amyotrophic Lateral Sclerosis/metabolism
KW - Mice
KW - Peptide Fragments/analysis
UR - http://www.mendeley.com/research/decreased-circulating-erbb4-ectodomain-fragments-readout-impaired-signaling-function-amyotrophic-lat
U2 - 10.1016/j.nbd.2018.12.021
DO - 10.1016/j.nbd.2018.12.021
M3 - Article
C2 - 30594809
SN - 0969-9961
VL - 124
SP - 428
EP - 438
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -