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      Characterization of the Contribution of Genetic Background and Gender to Disease Progression in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis: A Meta-Analysis

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          Abstract

          Background

          The SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS) is the most frequently used model to examine ALS pathophysiology. There is a lack of homogeneity in usage of the SOD1 G93A mouse, including differences in genetic background and gender, which could confound the field’s results.

          Objective

          In an analysis of 97 studies, we characterized the ALS progression for the high transgene copy control SOD1 G93A mouse on the basis of disease onset, overall lifespan, and disease duration for male and female mice on the B6SJL and C57BL/6J genetic backgrounds and quantified magnitudes of differences between groups.

          Methods

          Mean age at onset, onset assessment measure, disease duration, and overall lifespan data from each study were extracted and statistically modeled as the response of linear regression with the sex and genetic background factored as predictors. Additional examination was performed on differing experimental onset and endpoint assessment measures.

          Results

          C57BL/6 background mice show delayed onset of symptoms, increased lifespan, and an extended disease duration compared to their sex-matched B6SJL counterparts. Female B6SJL generally experience extended lifespan and delayed onset compared to their male counterparts, while female mice on the C57BL/6 background show delayed onset but no difference in survival compared to their male counterparts. Finally, different experimental protocols (tremor, rotarod, etc.) for onset determination result in notably different onset means.

          Conclusions

          Overall, the observed effect of sex on disease endpoints was smaller than that which can be attributed to the genetic background. The often-reported increase in lifespan for female mice was observed only for mice on the B6SJL background, implicating a strain-dependent effect of sex on disease progression that manifests despite identical mutant SOD1 expression.

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          Effects of gender in amyotrophic lateral sclerosis.

          Pamela McCombe, Ross D. Henderson (2010)
          There is evidence that amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is more common in men than in women and that gender influences the clinical features of the disease. The causes of this are unknown. This review examines the gender differences that are found in ALS and postulates reasons for these differences. A literature review of PubMed (with no date limits) was performed to find information about gender differences in the incidence, prevalence, and clinical features of ALS, using the search terms ALS or MND and gender or sex, ALS prevalence, and SOD1 mice and gender. Articles were reviewed for information about gender differences, together with other articles that were already known to the authors. The incidence and prevalence of ALS are greater in men than in women. This gender difference is seen in large studies that included all ALS patients (sporadic and familial), but is not seen when familial ALS is studied independently. Men predominate in the younger age groups of patients with ALS. Sporadic ALS has different clinical features in men and women, with men having a greater likelihood of onset in the spinal regions, and women tending to have onset in the bulbar region. Gender appears to have no clear effect on survival. In animals with superoxide dismutase 1 (sod1) mutations, sex does affect the clinical course of disease, with earlier onset in males. Possible reasons for the differences in ALS between men and women include different exposures to environmental toxins, different biological responses to exogenous toxins, and possibly underlying differences between the male and female nervous systems and different abilities to repair damage. There is a complex interaction between gender and clinical phenotypes in ALS. Understanding the causes of the gender differences could give clues to processes that modify the disease. Copyright © 2010. Published by EM Inc USA.
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            A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis

            Zhong-Tang Zhao, Dale Lange, Andrei Voustianiouk … (2006)
            Background The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization. Results SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-β-3 hydroxybutyrate (DBH), has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047). In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH. Conclusion This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain.
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              Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS.

              Thomas Gould, Robert Buss, Sharon Vinsant … (2006)
              The death of cranial and spinal motoneurons (MNs) is believed to be an essential component of the pathogenesis of amyotrophic lateral sclerosis (ALS). We tested this hypothesis by crossing Bax-deficient mice with mice expressing mutant superoxide dismutase 1 (SOD1), a transgenic model of familial ALS. Although Bax deletion failed to prevent neuromuscular denervation and mitochondrial vacuolization, MNs were completely rescued from mutant SOD1-mediated death. However, Bax deficiency extended lifespan and delayed the onset of motor dysfunction of SOD1 mutants, suggesting that Bax acts via a mechanism distinct from cell death activation. Consistent with this idea, Bax elimination delayed the onset of neuromuscular denervation, which began long before the activation of cell death proteins in SOD1 mutants. Additionally, we show that denervation preceded accumulation of mutant SOD1 within MNs and astrogliosis in the spinal cord, which are also both delayed in Bax-deficient SOD1 mutants. Interestingly, MNs exhibited mitochondrial abnormalities at the innervated neuromuscular junction at the onset of neuromuscular denervation. Additionally, both MN presynaptic terminals and terminal Schwann cells expressed high levels of mutant SOD1 before MNs withdrew their axons. Together, these data support the idea that clinical symptoms in the SOD1 G93A model of ALS result specifically from damage to the distal motor axon and not from activation of the death pathway, and cast doubt on the utility of anti-apoptotic therapies to combat ALS. Furthermore, they suggest a novel, cell death-independent role for Bax in facilitating mutant SOD1-mediated motor denervation.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101649948
                Journal ID (pubmed-jr-id): 43480
                Journal ID (nlm-ta): J Neuromuscul Dis
                Journal ID (iso-abbrev): J Neuromuscul Dis
                Title: Journal of neuromuscular diseases
                ISSN (Print): 2214-3599
                ISSN (Electronic): 2214-3602
                Publication date Nihms-submitted: 28 July 2015
                Publication date (Electronic): 4 June 2015
                Publication date (Print): 2015
                Publication date PMC-release: 19 November 2015
                Volume: 2
                Issue: 2
                Pages: 137-150
                Affiliations
                Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA
                Author notes
                [* ]Correspondence to: Cassie S. Mitchell, Ph.D., Senior Research Faculty, Georgia Institute of Technology & Emory University School of Medicine, 313 Ferst Drive, Atlanta, GA 30332, USA. Tel.: +1 404 276 8475; cassie.mitchell@ 123456bme.gatech.edu . http://orcid.org/0000-0002-5472-6355
                Article
                Manuscript ID: NIHMS710633
                DOI: 10.3233/JND-140068
                PMC ID: 4652798
                PubMed ID: 26594635
                SO-VID: 28c17850-62ef-4944-939f-d8d0f0496450
                License:

                This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License.

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                Subject: Article

                Keywords: lou gehrig’s disease,als,amyotrophic lateral sclerosis,motoneuron disease,transgenic mice,rotarod,hindlimb tremor,forelimb tremor
                Data availability:
                Keywords: lou gehrig’s disease, als, amyotrophic lateral sclerosis, motoneuron disease, transgenic mice, rotarod, hindlimb tremor, forelimb tremor

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