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Different Human Copper-Zinc Superoxide Dismutase Mutants, SOD1(G93A) and SOD1(H46R), Exert Distinct Harmful Effects on Gross Phenotype in Mice
Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of fatal neurodegenerative diseases characterized by a selective loss of motor neurons in the brain and spinal cord. Creation of transgenic mice expressing mutant Cu/Zn superoxide dismutase (SOD1), as ALS models, has made an enormous impac...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306410/ https://www.ncbi.nlm.nih.gov/pubmed/22438926 http://dx.doi.org/10.1371/journal.pone.0033409 |
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author | Pan, Lei Yoshii, Yasuhiro Otomo, Asako Ogawa, Haruko Iwasaki, Yasuo Shang, Hui-Fang Hadano, Shinji |
author_facet | Pan, Lei Yoshii, Yasuhiro Otomo, Asako Ogawa, Haruko Iwasaki, Yasuo Shang, Hui-Fang Hadano, Shinji |
author_sort | Pan, Lei |
collection | PubMed |
description | Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of fatal neurodegenerative diseases characterized by a selective loss of motor neurons in the brain and spinal cord. Creation of transgenic mice expressing mutant Cu/Zn superoxide dismutase (SOD1), as ALS models, has made an enormous impact on progress of the ALS studies. Recently, it has been recognized that genetic background and gender affect many physiological and pathological phenotypes. However, no systematic studies focusing on such effects using ALS models other than SOD1(G93A) mice have been conducted. To clarify the effects of genetic background and gender on gross phenotypes among different ALS models, we here conducted a comparative analysis of growth curves and lifespans using congenic lines of SOD1(G93A) and SOD1(H46R) mice on two different genetic backgrounds; C57BL/6N (B6) and FVB/N (FVB). Copy number of the transgene and their expression between SOD1(G93A) and SOD1(H46R) lines were comparable. B6 congenic mutant SOD1 transgenic lines irrespective of their mutation and gender differences lived longer than corresponding FVB lines. Notably, the G93A mutation caused severer disease phenotypes than did the H46R mutation, where SOD1(G93A) mice, particularly on a FVB background, showed more extensive body weight loss and earlier death. Gender effect on survival also solely emerged in FVB congenic SOD1(G93A) mice. Conversely, consistent with our previous study using B6 lines, lack of Als2, a murine homolog for the recessive juvenile ALS causative gene, in FVB congenic SOD1(H46R), but not SOD1(G93A), mice resulted in an earlier death, implying a genetic background-independent but mutation-dependent phenotypic modification. These results indicate that SOD1(G93A)- and SOD1(H46R)-mediated toxicity and their associated pathogenic pathways are not identical. Further, distinctive injurious effects resulted from different SOD1 mutations, which are associated with genetic background and/or gender, suggests the presence of several genetic modifiers of disease expression in the mouse genome. |
format | Online Article Text |
id | pubmed-3306410 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33064102012-03-21 Different Human Copper-Zinc Superoxide Dismutase Mutants, SOD1(G93A) and SOD1(H46R), Exert Distinct Harmful Effects on Gross Phenotype in Mice Pan, Lei Yoshii, Yasuhiro Otomo, Asako Ogawa, Haruko Iwasaki, Yasuo Shang, Hui-Fang Hadano, Shinji PLoS One Research Article Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of fatal neurodegenerative diseases characterized by a selective loss of motor neurons in the brain and spinal cord. Creation of transgenic mice expressing mutant Cu/Zn superoxide dismutase (SOD1), as ALS models, has made an enormous impact on progress of the ALS studies. Recently, it has been recognized that genetic background and gender affect many physiological and pathological phenotypes. However, no systematic studies focusing on such effects using ALS models other than SOD1(G93A) mice have been conducted. To clarify the effects of genetic background and gender on gross phenotypes among different ALS models, we here conducted a comparative analysis of growth curves and lifespans using congenic lines of SOD1(G93A) and SOD1(H46R) mice on two different genetic backgrounds; C57BL/6N (B6) and FVB/N (FVB). Copy number of the transgene and their expression between SOD1(G93A) and SOD1(H46R) lines were comparable. B6 congenic mutant SOD1 transgenic lines irrespective of their mutation and gender differences lived longer than corresponding FVB lines. Notably, the G93A mutation caused severer disease phenotypes than did the H46R mutation, where SOD1(G93A) mice, particularly on a FVB background, showed more extensive body weight loss and earlier death. Gender effect on survival also solely emerged in FVB congenic SOD1(G93A) mice. Conversely, consistent with our previous study using B6 lines, lack of Als2, a murine homolog for the recessive juvenile ALS causative gene, in FVB congenic SOD1(H46R), but not SOD1(G93A), mice resulted in an earlier death, implying a genetic background-independent but mutation-dependent phenotypic modification. These results indicate that SOD1(G93A)- and SOD1(H46R)-mediated toxicity and their associated pathogenic pathways are not identical. Further, distinctive injurious effects resulted from different SOD1 mutations, which are associated with genetic background and/or gender, suggests the presence of several genetic modifiers of disease expression in the mouse genome. Public Library of Science 2012-03-16 /pmc/articles/PMC3306410/ /pubmed/22438926 http://dx.doi.org/10.1371/journal.pone.0033409 Text en Pan et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Pan, Lei Yoshii, Yasuhiro Otomo, Asako Ogawa, Haruko Iwasaki, Yasuo Shang, Hui-Fang Hadano, Shinji Different Human Copper-Zinc Superoxide Dismutase Mutants, SOD1(G93A) and SOD1(H46R), Exert Distinct Harmful Effects on Gross Phenotype in Mice |
title | Different Human Copper-Zinc Superoxide Dismutase Mutants, SOD1(G93A) and SOD1(H46R), Exert Distinct Harmful Effects on Gross Phenotype in Mice |
title_full | Different Human Copper-Zinc Superoxide Dismutase Mutants, SOD1(G93A) and SOD1(H46R), Exert Distinct Harmful Effects on Gross Phenotype in Mice |
title_fullStr | Different Human Copper-Zinc Superoxide Dismutase Mutants, SOD1(G93A) and SOD1(H46R), Exert Distinct Harmful Effects on Gross Phenotype in Mice |
title_full_unstemmed | Different Human Copper-Zinc Superoxide Dismutase Mutants, SOD1(G93A) and SOD1(H46R), Exert Distinct Harmful Effects on Gross Phenotype in Mice |
title_short | Different Human Copper-Zinc Superoxide Dismutase Mutants, SOD1(G93A) and SOD1(H46R), Exert Distinct Harmful Effects on Gross Phenotype in Mice |
title_sort | different human copper-zinc superoxide dismutase mutants, sod1(g93a) and sod1(h46r), exert distinct harmful effects on gross phenotype in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306410/ https://www.ncbi.nlm.nih.gov/pubmed/22438926 http://dx.doi.org/10.1371/journal.pone.0033409 |
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