MnSOD deficiency has a differential effect on disease progression in two different ALS mutant mouse models

Florian L. Muller, Yuhong Liu, Amanda Jernigan, David Borchelt, Arlan Richardson, Holly Van Remmen

Research output: Contribution to journalArticle

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Abstract

Mitochondrial dysfunction and oxidative stress are thought to participate in the pathogenesis of amyotrophic lateral sclerosis (ALS). The purpose of this study was to determine the effect of reduced mitochondrial antioxidant defense on lifespan and disease progression in two mouse models of familial ALS (G93A and H46R/H48Q mutant lines) that represent pseudo-wildtype and metal-deficient ALS mutants, respectively. The metal-deficient H46R/H48Q mutant differs from the G93A mutant in that it cannot bind copper in the active site and thus lacks SOD activity. We crossed each of these mutant lines with mice deficient in the mitochondrial matrix antioxidant enzyme MnSOD (Sod2+/- mice). In both high (G93A1Gur) and low (G93ADL) copy G93A strains, MnSOD deficiency caused a decrease in lifespan that was associated with a reduced disease duration rather than earlier disease onset. In contrast, MnSOD deficiency had no effect on lifespan or disease parameters of H46R/H48Q mutant mice. MnSOD deficiency thus has a differential effect on disease progression in different mutant SOD1 ALS mouse models, suggesting that different ALS-causing mutations in SOD1 result in disease progression by at least proximally different mechanisms/pathways.

Original languageEnglish (US)
Pages (from-to)1173-1183
Number of pages11
JournalMuscle and Nerve
Volume38
Issue number3
DOIs
StatePublished - Sep 2008

Fingerprint

Amyotrophic Lateral Sclerosis
Disease Progression
Antioxidants
Metals
Copper
Catalytic Domain
Oxidative Stress
Mutation
Enzymes

Keywords

  • ALS
  • G93A
  • H46R/H48Q
  • MnSOD
  • Oxidative stress

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Muller, F. L., Liu, Y., Jernigan, A., Borchelt, D., Richardson, A., & Van Remmen, H. (2008). MnSOD deficiency has a differential effect on disease progression in two different ALS mutant mouse models. Muscle and Nerve, 38(3), 1173-1183. https://doi.org/10.1002/mus.21049

MnSOD deficiency has a differential effect on disease progression in two different ALS mutant mouse models. / Muller, Florian L.; Liu, Yuhong; Jernigan, Amanda; Borchelt, David; Richardson, Arlan; Van Remmen, Holly.

In: Muscle and Nerve, Vol. 38, No. 3, 09.2008, p. 1173-1183.

Research output: Contribution to journalArticle

Muller, FL, Liu, Y, Jernigan, A, Borchelt, D, Richardson, A & Van Remmen, H 2008, 'MnSOD deficiency has a differential effect on disease progression in two different ALS mutant mouse models', Muscle and Nerve, vol. 38, no. 3, pp. 1173-1183. https://doi.org/10.1002/mus.21049
Muller, Florian L. ; Liu, Yuhong ; Jernigan, Amanda ; Borchelt, David ; Richardson, Arlan ; Van Remmen, Holly. / MnSOD deficiency has a differential effect on disease progression in two different ALS mutant mouse models. In: Muscle and Nerve. 2008 ; Vol. 38, No. 3. pp. 1173-1183.
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