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A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune cell...

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Autores principales: Vallarola, Antonio, Tortarolo, Massimo, De Gioia, Roberta, Iamele, Luisa, de Jonge, Hugo, de Nola, Giovanni, Bovio, Enrica, Pasetto, Laura, Bonetto, Valentina, Freschi, Mattia, Bendotti, Caterina, Gherardi, Ermanno
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696450/
https://www.ncbi.nlm.nih.gov/pubmed/33198383
http://dx.doi.org/10.3390/ijms21228542
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author Vallarola, Antonio
Tortarolo, Massimo
De Gioia, Roberta
Iamele, Luisa
de Jonge, Hugo
de Nola, Giovanni
Bovio, Enrica
Pasetto, Laura
Bonetto, Valentina
Freschi, Mattia
Bendotti, Caterina
Gherardi, Ermanno
author_facet Vallarola, Antonio
Tortarolo, Massimo
De Gioia, Roberta
Iamele, Luisa
de Jonge, Hugo
de Nola, Giovanni
Bovio, Enrica
Pasetto, Laura
Bonetto, Valentina
Freschi, Mattia
Bendotti, Caterina
Gherardi, Ermanno
author_sort Vallarola, Antonio
collection PubMed
description Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune cell function. We recently developed a novel recombinant MET agonist optimized for therapy, designated K1K1. K1K1 was ten times more potent than HGF/SF in preventing MN loss in an in vitro model of ALS. Treatments with K1K1 delayed the onset of muscular impairment and reduced MN loss and skeletal muscle denervation of superoxide dismutase 1 G93A (SOD1G93A) mice. This effect was associated with increased levels of phospho-extracellular signal-related kinase (pERK) in the spinal cord and sciatic nerves and the activation of non-myelinating Schwann cells. Moreover, reduced activated microglia and astroglia, lower T cells infiltration and increased interleukin 4 (IL4) levels were found in the lumbar spinal cord of K1K1 treated mice. K1K1 treatment also prevented the infiltration of T cells in skeletal muscle of SOD1G93A mice. All these protective effects were lost on long-term treatment suggesting a mechanism of drug tolerance. These data provide a rational justification for further exploring the long-term loss of K1K1 efficacy in the perspective of providing a potential treatment for ALS.
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spelling pubmed-76964502020-11-29 A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation Vallarola, Antonio Tortarolo, Massimo De Gioia, Roberta Iamele, Luisa de Jonge, Hugo de Nola, Giovanni Bovio, Enrica Pasetto, Laura Bonetto, Valentina Freschi, Mattia Bendotti, Caterina Gherardi, Ermanno Int J Mol Sci Article Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune cell function. We recently developed a novel recombinant MET agonist optimized for therapy, designated K1K1. K1K1 was ten times more potent than HGF/SF in preventing MN loss in an in vitro model of ALS. Treatments with K1K1 delayed the onset of muscular impairment and reduced MN loss and skeletal muscle denervation of superoxide dismutase 1 G93A (SOD1G93A) mice. This effect was associated with increased levels of phospho-extracellular signal-related kinase (pERK) in the spinal cord and sciatic nerves and the activation of non-myelinating Schwann cells. Moreover, reduced activated microglia and astroglia, lower T cells infiltration and increased interleukin 4 (IL4) levels were found in the lumbar spinal cord of K1K1 treated mice. K1K1 treatment also prevented the infiltration of T cells in skeletal muscle of SOD1G93A mice. All these protective effects were lost on long-term treatment suggesting a mechanism of drug tolerance. These data provide a rational justification for further exploring the long-term loss of K1K1 efficacy in the perspective of providing a potential treatment for ALS. MDPI 2020-11-12 /pmc/articles/PMC7696450/ /pubmed/33198383 http://dx.doi.org/10.3390/ijms21228542 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vallarola, Antonio
Tortarolo, Massimo
De Gioia, Roberta
Iamele, Luisa
de Jonge, Hugo
de Nola, Giovanni
Bovio, Enrica
Pasetto, Laura
Bonetto, Valentina
Freschi, Mattia
Bendotti, Caterina
Gherardi, Ermanno
A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation
title A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation
title_full A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation
title_fullStr A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation
title_full_unstemmed A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation
title_short A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation
title_sort novel hgf/sf receptor (met) agonist transiently delays the disease progression in an amyotrophic lateral sclerosis mouse model by promoting neuronal survival and dampening the immune dysregulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696450/
https://www.ncbi.nlm.nih.gov/pubmed/33198383
http://dx.doi.org/10.3390/ijms21228542
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