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Different human copper-zinc superoxide dismutase mutants, SOD1G93A and SOD1H46R, exert distinct harmful effects on gross phenotype in mice.

Pan L, Yoshii Y, Otomo A, Ogawa H, Iwasaki Y, Shang HF, Hadano S - PLoS ONE (2012)

Bottom Line: 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.These results indicate that SOD1(G93A)- and SOD1(H46R)-mediated toxicity and their associated pathogenic pathways are not identical.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

ABSTRACT
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.

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Effect of different types of the SOD1 mutation on survival.(A) Survival curves for C57BL/6 (B6) congenic SOD1G93A transgenic female mice (B6_G93A F) (closed circle: n = 19) and B6 congenic SOD1H46R transgenic female mice (B6_H46R F) (open square: n = 31). (B) Survival curves for B6 congenic SOD1G93A transgenic male mice (B6_G93A M) (closed circle: n = 15) and B6 congenic SOD1H46R transgenic male mice (B6_H46R M) (open square: n = 63). (C) Survival curves for FVB/N (FVB) congenic SOD1G93A transgenic female mice (FVB_G93A F) (closed circle: n = 20) and FVB congenic SOD1H46R transgenic female mice (FVB_H46R F) (open square: n = 20). (D) Survival curves for FVB congenic SOD1G93A transgenic male mice (FVB_G93A M) (closed circle: n = 17) and FVB congenic SOD1H46R transgenic male mice (FVB_H46R M) (open square: n = 27). Kaplan-Meier analysis with Log-rank (Mantel-Cox) test identifies significant differences in survival between B6_G93A F and B6_H46R F (p = 0.0210), B6_G93A M and B6_H46R M (p = 0.0004), FVB_G93A F and FVB_H46R F (p<0.0001), and FVB_G93A M and FVB_H46R M (p<0.0001).
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pone-0033409-g006: Effect of different types of the SOD1 mutation on survival.(A) Survival curves for C57BL/6 (B6) congenic SOD1G93A transgenic female mice (B6_G93A F) (closed circle: n = 19) and B6 congenic SOD1H46R transgenic female mice (B6_H46R F) (open square: n = 31). (B) Survival curves for B6 congenic SOD1G93A transgenic male mice (B6_G93A M) (closed circle: n = 15) and B6 congenic SOD1H46R transgenic male mice (B6_H46R M) (open square: n = 63). (C) Survival curves for FVB/N (FVB) congenic SOD1G93A transgenic female mice (FVB_G93A F) (closed circle: n = 20) and FVB congenic SOD1H46R transgenic female mice (FVB_H46R F) (open square: n = 20). (D) Survival curves for FVB congenic SOD1G93A transgenic male mice (FVB_G93A M) (closed circle: n = 17) and FVB congenic SOD1H46R transgenic male mice (FVB_H46R M) (open square: n = 27). Kaplan-Meier analysis with Log-rank (Mantel-Cox) test identifies significant differences in survival between B6_G93A F and B6_H46R F (p = 0.0210), B6_G93A M and B6_H46R M (p = 0.0004), FVB_G93A F and FVB_H46R F (p<0.0001), and FVB_G93A M and FVB_H46R M (p<0.0001).

Mentions: We next examined whether the different SOD1 mutations affected survival in mice on the same genetic background and gender. Kaplan-Meier survival analysis revealed that the G93A mutation resulted in a shorter lifespan than did the H46R mutation in both B6 and FVB lines irrespective of gender (Figure 6A–D). It is noted that such toxic effects of the G93A mutation were more obvious in mice on a FVB background (Figure 6C and D). The data suggest that the G93A mutation in SOD1 causes a severer disease phenotype than does the H46R mutation, and support the notion that FVB congenic mice are more susceptible to the SOD1G93A-mediated toxic insults than B6 lines.


Different human copper-zinc superoxide dismutase mutants, SOD1G93A and SOD1H46R, exert distinct harmful effects on gross phenotype in mice.

Pan L, Yoshii Y, Otomo A, Ogawa H, Iwasaki Y, Shang HF, Hadano S - PLoS ONE (2012)

Effect of different types of the SOD1 mutation on survival.(A) Survival curves for C57BL/6 (B6) congenic SOD1G93A transgenic female mice (B6_G93A F) (closed circle: n = 19) and B6 congenic SOD1H46R transgenic female mice (B6_H46R F) (open square: n = 31). (B) Survival curves for B6 congenic SOD1G93A transgenic male mice (B6_G93A M) (closed circle: n = 15) and B6 congenic SOD1H46R transgenic male mice (B6_H46R M) (open square: n = 63). (C) Survival curves for FVB/N (FVB) congenic SOD1G93A transgenic female mice (FVB_G93A F) (closed circle: n = 20) and FVB congenic SOD1H46R transgenic female mice (FVB_H46R F) (open square: n = 20). (D) Survival curves for FVB congenic SOD1G93A transgenic male mice (FVB_G93A M) (closed circle: n = 17) and FVB congenic SOD1H46R transgenic male mice (FVB_H46R M) (open square: n = 27). Kaplan-Meier analysis with Log-rank (Mantel-Cox) test identifies significant differences in survival between B6_G93A F and B6_H46R F (p = 0.0210), B6_G93A M and B6_H46R M (p = 0.0004), FVB_G93A F and FVB_H46R F (p<0.0001), and FVB_G93A M and FVB_H46R M (p<0.0001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3306410&req=5

pone-0033409-g006: Effect of different types of the SOD1 mutation on survival.(A) Survival curves for C57BL/6 (B6) congenic SOD1G93A transgenic female mice (B6_G93A F) (closed circle: n = 19) and B6 congenic SOD1H46R transgenic female mice (B6_H46R F) (open square: n = 31). (B) Survival curves for B6 congenic SOD1G93A transgenic male mice (B6_G93A M) (closed circle: n = 15) and B6 congenic SOD1H46R transgenic male mice (B6_H46R M) (open square: n = 63). (C) Survival curves for FVB/N (FVB) congenic SOD1G93A transgenic female mice (FVB_G93A F) (closed circle: n = 20) and FVB congenic SOD1H46R transgenic female mice (FVB_H46R F) (open square: n = 20). (D) Survival curves for FVB congenic SOD1G93A transgenic male mice (FVB_G93A M) (closed circle: n = 17) and FVB congenic SOD1H46R transgenic male mice (FVB_H46R M) (open square: n = 27). Kaplan-Meier analysis with Log-rank (Mantel-Cox) test identifies significant differences in survival between B6_G93A F and B6_H46R F (p = 0.0210), B6_G93A M and B6_H46R M (p = 0.0004), FVB_G93A F and FVB_H46R F (p<0.0001), and FVB_G93A M and FVB_H46R M (p<0.0001).
Mentions: We next examined whether the different SOD1 mutations affected survival in mice on the same genetic background and gender. Kaplan-Meier survival analysis revealed that the G93A mutation resulted in a shorter lifespan than did the H46R mutation in both B6 and FVB lines irrespective of gender (Figure 6A–D). It is noted that such toxic effects of the G93A mutation were more obvious in mice on a FVB background (Figure 6C and D). The data suggest that the G93A mutation in SOD1 causes a severer disease phenotype than does the H46R mutation, and support the notion that FVB congenic mice are more susceptible to the SOD1G93A-mediated toxic insults than B6 lines.

Bottom Line: 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.These results indicate that SOD1(G93A)- and SOD1(H46R)-mediated toxicity and their associated pathogenic pathways are not identical.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus