Reduction in hSOD1 copy number significantly impacts ALS phenotype presentation in G37R (line 29) mice: implications for the assessment of putative therapeutic agents

Journal of Negative Results in Biomedicine

Christopher A Shaw²  Grace Lee³  Pierre Zwiegers¹ 

[1] Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada;Program in Neuroscience, University of British Columbia, Vancouver, Canada;Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, Canada

关键词: G37R;    G93A;    Copy number variation;    ALS;    SOD1;   

Others  :  1133143
DOI  :  10.1186/1477-5751-13-14

 received in 2014-05-13, accepted in 2014-07-31,  发布年份 2014

【 摘 要 】

Background

In vivo animal models of familial amyotrophic lateral sclerosis (fALS) are widely used to delineate the potential role that genetic mutations play in the neurodegenerative process. While these models are extensively used for establishing the safety and efficacy of putative therapeutics during pre-clinical development, effective clinical translation of pharmacological interventions has been largely unsuccessful.

Results

In this report we compare a recent cohort of G37R (line 29) mice generated from mating wild-type females with transgenic males obtained commercially to a previous set of offspring produced with transgenic male breeders from a colony established at a local collaborator’s facility. Commercially derived progeny presented with a tightly clustered genomic signature for the mutant human superoxide dismutase1 transgene (hSOD1) locus, and exhibited a greater than two-fold reduction in the number of transgene copies present in the genome compared to offspring derived locally. Decrease in transgene levels corresponded with delayed ALS progression and a significant increase in overall lifespan (146%).

Conclusions

These results highlight some key challenges inherent to the use of G37R (line 29) animals in pre-clinical studies for the development of ALS therapeutics. Without stringent assessment of mutant SOD1 copy number/protein levels, heterogeneity of transgene levels within cohorts may influence the behavioural and pathological presentation of disease and thus calls to question the validity of any detected therapeutic effects. Nuanced changes in mutant SOD1 copy number that currently remain unreported may undermine research endeavours, delay efforts for clinical translation, and compromise the rigor of animal studies by limiting reproducibility amongst research groups.

【 授权许可】

   
2014 Zwiegers et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Byrne S, Walsh C, Lynch C, Bede P, Elamin M, Kenna K, McLaughlin R, Hardiman O: Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2011, 82:623-627.
• [2]Amyotrophic Lateral Sclerosis Online Genetic Database [http://alsod.iop.kcl.ac.uk/Overview/gene.aspx?gene_id=SOD1 webcite]
• [3]Saccon R, Bunton-Stasyshyn R, Fisher E, Fratta P: Is SOD1 loss of function involved in amyotrophic lateral sclerosis? Brain 2013, 136:2342-2358.
• [4]Kabashi E, Valdmanis P, Dion P, Rouleau G: Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis? Ann Neurology 2007, 62:553-559.
• [5]Kato S: Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences. Acta Neuropathol 2008, 115:97-114.
• [6]Joyce P, Fratta P, Fisher E, Acevedo-Arozena A: SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. Mamm Genome 2011, 22:420-448.
• [7]Gurney M: The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies. J Neurol Sci 1997, 152(Suppl. 1):S67-S73.
• [8]Lee G, Shaw CA: Early exposure to environmental toxin contributes to neuronal vulnerability and axonal pathology in familial ALS. Neurosci Med 2012, 3:404-417.
• [9]Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, Chen W, Zhai P, Sufit RL, Siddique T: Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 1994, 264:1772-1775.
• [10]Wong P, Pardo C, Borchelt D, Lee M, Copeland N, Jenkins N, Sisodia S, Cleveland D, Price D: An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 1995, 14(6):1105-1116.
• [11]Bruijn L, Becher M, Lee M, Anderson K, Jenkins N, Copeland N, Sisodia S, Rothstein J, Borchelt D, Price D, Cleveland D: ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 1997, 18:327-338.
• [12]Jonsson P, Graffmo K, Brännström T, Nilsson P, Andersen P, Marklund S: Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1. J Neuropathol Exp Neurol 2006, 65:1126-1136.
• [13]Dal Canto M, Gurney M: Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol 1994, 145:1271-1279.
• [14]Dal Canto M, Gurney M: Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu, Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res 1995, 676:25-40.
• [15]Chui A, Zhai P, Dal Canto M, Peters T, Kwon Y, Prattis S, Gurney M: Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. Mol Cell Neurosci 1995, 6:349-362.
• [16]Zhang B, Tu P, Abtahian F, Trojanowski J, Lee V: Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol 1997, 139(5):1307-1315.
• [17]Alexander G, Erwin K, Byers N, Deitch J, Augelli B, Blankenhorn E, Heiman-Patterson T: Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS. Brain Res Mol Brain Res 2004, 130:7-15.
• [18]Benatar M: Lost in translation: treatment trials in the SOD1 mouse and in human ALS. Neurobiol Dis 2007, 26:1-13.
• [19]Wilkins HM, Bouchard RJ, Lorenzon NM Linseman DA: Poor Correlation Between Drug Efficacies in the Mutant SOD1 Mouse Model Versus Clinical Trials of ALS Necessitates the Development of Novel Animal Models for Sporadic Motor Neuron Disease. In Horizons in Neuroscience Research Volume 5. Edited by Costa A, Villalba E. New York: Nova Science Publishers, Inc; 2011:1-39.
• [20]Nirmalananthan N, Greensmith L: Amyotrophic lateral sclerosis: recent advances and future therapies. Curr Opin Neurol 2005, 18:712-719.
• [21]Scott S, Kranz J, Cole J, Lincecum J, Thompson K, Kelly N, Bostrom A, Theodoss J, Al-Nakhala B, Vieira F, Ramasubbu J, Heywood J: Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler 2008, 9(1):4-15.
• [22]Ludolph A, Bendotti C, Blaugrund E, Chio A, Greensmith L, Loeffler JP, Mead R, Niessen H, Petri S, Pradat PF, Robberecht W, Ruegg M, Schwalenstöcker B, Stiller D, Berg L, Vieira F, Horsten S: Guidelines for preclinical animal research in ALS/MND: a consensus meeting. Amyotroph Lateral Scler 2010, 11(1–2):38-45.
• [23]Cervetto C, Frattaroli D, Maura G, Marcoli M: Motor neuron dysfunction in a mouse model of ALS: gender-dependent effect of P2X7 antagonism. Toxicology 2013, 311:69-77.
• [24]Ezzi S, Larivière R, Urushitani M, Julien JP: Neuronal over-expression of chromogranin A accelerates disease onset in a mouse model of ALS. J Neurochem 2010, 115:1102-1111.
• [25]Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, Reaume AG, Scott RW, Cleveland DW: Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant Independent from wild-type SOD1. Science 1998, 281:1851-1853.
• [26]Pasinelli P, Brown R: Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 2006, 7(9):710-723.
• [27]Gros-Louis F, Gaspar C, Rouleau GA: Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta 2006, 1762:956-972.
• [28]Hand C, Rouleau G: Familial amyotrophic lateral sclerosis. Muscle Nerve 2002, 25:135-159.
• [29]Liu HN, Sanelli T, Horne P, Pioro EP, Strong MJ, Rogaeva E, Bilboa J, Zinman L, Robertson J: Lack of evidence of monomer/misfolded superoxide dismutase-1 in sporadic amyotrophic lateral sclerosis. Ann Neurol 2009, 66(1):75-80.
• [30]Mackenzie I, Bigio E, Ince P, Geser F, Neumann M, Cairns N, Kwong L, Forman M, Ravits J, Stewart H, Eisen A, McClusky L, Kretzschmar H, Monoranu C, Highley J, Kirby J, Siddique T, Shaw P, Lee V, Trojanowski J: Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 2007, 61(5):427-434.