c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.

<h4>Background</h4>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive death of motor neurons. Although the pathogenesis of ALS remains unclear, several cellular processes are known to be involved, including apoptosis. A previous study re...

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Autores principales: Ryu Katsumata, Shinsuke Ishigaki, Masahisa Katsuno, Kaori Kawai, Jun Sone, Zhe Huang, Hiroaki Adachi, Fumiaki Tanaka, Fumihiko Urano, Gen Sobue
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spelling oai:doaj.org-article:95e88ca923da4d248ec144fba0ba317b2021-11-18T08:14:02Zc-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.1932-620310.1371/journal.pone.0046185https://doaj.org/article/95e88ca923da4d248ec144fba0ba317b2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23049975/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive death of motor neurons. Although the pathogenesis of ALS remains unclear, several cellular processes are known to be involved, including apoptosis. A previous study revealed the apoptosis-related gene c-Abl to be upregulated in sporadic ALS motor neurons.<h4>Methodology/findings</h4>We investigated the possibility that c-Abl activation is involved in the progression of ALS and that c-Abl inhibition is potentially a therapeutic strategy for ALS. Using a mouse motor neuron cell line, we found that mutation of Cu/Zn-superoxide dismutase-1 (SOD1), which is one of the causative genes of familial ALS, induced the upregulation of c-Abl and decreased cell viability, and that the c-Abl inhibitor dasatinib inhibited cytotoxicity. Activation of c-Abl with a concomitant increase in activated caspase-3 was observed in the lumbar spine of G93A-SOD1 transgenic mice (G93A mice), a widely used model of ALS. The survival of G93A mice was improved by oral administration of dasatinib, which also decreased c-Abl phosphorylation, inactivated caspase-3, and improved the innervation status of neuromuscular junctions. In addition, c-Abl expression in postmortem spinal cord tissues from sporadic ALS patients was increased by 3-fold compared with non-ALS patients.<h4>Conclusions/significance</h4>The present results suggest that c-Abl is a potential therapeutic target for ALS and that the c-Abl inhibitor dasatinib has neuroprotective properties in vitro and in vivo.Ryu KatsumataShinsuke IshigakiMasahisa KatsunoKaori KawaiJun SoneZhe HuangHiroaki AdachiFumiaki TanakaFumihiko UranoGen SobuePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 9, p e46185 (2012)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Ryu Katsumata
Shinsuke Ishigaki
Masahisa Katsuno
Kaori Kawai
Jun Sone
Zhe Huang
Hiroaki Adachi
Fumiaki Tanaka
Fumihiko Urano
Gen Sobue
c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.
description <h4>Background</h4>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive death of motor neurons. Although the pathogenesis of ALS remains unclear, several cellular processes are known to be involved, including apoptosis. A previous study revealed the apoptosis-related gene c-Abl to be upregulated in sporadic ALS motor neurons.<h4>Methodology/findings</h4>We investigated the possibility that c-Abl activation is involved in the progression of ALS and that c-Abl inhibition is potentially a therapeutic strategy for ALS. Using a mouse motor neuron cell line, we found that mutation of Cu/Zn-superoxide dismutase-1 (SOD1), which is one of the causative genes of familial ALS, induced the upregulation of c-Abl and decreased cell viability, and that the c-Abl inhibitor dasatinib inhibited cytotoxicity. Activation of c-Abl with a concomitant increase in activated caspase-3 was observed in the lumbar spine of G93A-SOD1 transgenic mice (G93A mice), a widely used model of ALS. The survival of G93A mice was improved by oral administration of dasatinib, which also decreased c-Abl phosphorylation, inactivated caspase-3, and improved the innervation status of neuromuscular junctions. In addition, c-Abl expression in postmortem spinal cord tissues from sporadic ALS patients was increased by 3-fold compared with non-ALS patients.<h4>Conclusions/significance</h4>The present results suggest that c-Abl is a potential therapeutic target for ALS and that the c-Abl inhibitor dasatinib has neuroprotective properties in vitro and in vivo.
format article
author Ryu Katsumata
Shinsuke Ishigaki
Masahisa Katsuno
Kaori Kawai
Jun Sone
Zhe Huang
Hiroaki Adachi
Fumiaki Tanaka
Fumihiko Urano
Gen Sobue
author_facet Ryu Katsumata
Shinsuke Ishigaki
Masahisa Katsuno
Kaori Kawai
Jun Sone
Zhe Huang
Hiroaki Adachi
Fumiaki Tanaka
Fumihiko Urano
Gen Sobue
author_sort Ryu Katsumata
title c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.
title_short c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.
title_full c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.
title_fullStr c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.
title_full_unstemmed c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis.
title_sort c-abl inhibition delays motor neuron degeneration in the g93a mouse, an animal model of amyotrophic lateral sclerosis.
publisher Public Library of Science (PLoS)
publishDate 2012
url https://doaj.org/article/95e88ca923da4d248ec144fba0ba317b
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