Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein resp...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4545826?pdf=render |
| _version_ | 1818132715476615168 |
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| author | Fernando G Vieira Qinggong Ping Andy J Moreno Joshua D Kidd Kenneth Thompson Bingbing Jiang John M Lincecum Monica Z Wang Gerard S De Zutter Valerie R Tassinari Beth Levine Theo Hatzipetros Alan Gill Steven Perrin |
| author_facet | Fernando G Vieira Qinggong Ping Andy J Moreno Joshua D Kidd Kenneth Thompson Bingbing Jiang John M Lincecum Monica Z Wang Gerard S De Zutter Valerie R Tassinari Beth Levine Theo Hatzipetros Alan Gill Steven Perrin |
| author_sort | Fernando G Vieira |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha). Here we demonstrate that guanabenz is protective in fibroblasts expressing G93A mutant SOD1 when they are exposed to tunicamycin mediated ER stress. However, in contrast to other reports, guanabenz treatment accelerated ALS-like disease progression in a strain of mutant SOD1 transgenic ALS mice. This study highlights challenges of pharmacological interventions of cellular stress responses in whole animal models of ALS. |
| first_indexed | 2024-12-11T08:41:14Z |
| format | Article |
| id | doaj.art-f052d1fb3a364d89b9b51dacb83c5f26 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T08:41:14Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f052d1fb3a364d89b9b51dacb83c5f262022-12-22T01:14:15ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01108e013557010.1371/journal.pone.0135570Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS.Fernando G VieiraQinggong PingAndy J MorenoJoshua D KiddKenneth ThompsonBingbing JiangJohn M LincecumMonica Z WangGerard S De ZutterValerie R TassinariBeth LevineTheo HatzipetrosAlan GillSteven PerrinAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha). Here we demonstrate that guanabenz is protective in fibroblasts expressing G93A mutant SOD1 when they are exposed to tunicamycin mediated ER stress. However, in contrast to other reports, guanabenz treatment accelerated ALS-like disease progression in a strain of mutant SOD1 transgenic ALS mice. This study highlights challenges of pharmacological interventions of cellular stress responses in whole animal models of ALS.http://europepmc.org/articles/PMC4545826?pdf=render |
| spellingShingle | Fernando G Vieira Qinggong Ping Andy J Moreno Joshua D Kidd Kenneth Thompson Bingbing Jiang John M Lincecum Monica Z Wang Gerard S De Zutter Valerie R Tassinari Beth Levine Theo Hatzipetros Alan Gill Steven Perrin Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS. PLoS ONE |
| title | Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS. |
| title_full | Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS. |
| title_fullStr | Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS. |
| title_full_unstemmed | Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS. |
| title_short | Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS. |
| title_sort | guanabenz treatment accelerates disease in a mutant sod1 mouse model of als |
| url | http://europepmc.org/articles/PMC4545826?pdf=render |
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