Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: A window of opportunity in the search for genetic modifiers

Abstract

Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A. In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1. Expression of G93A-hSOD1Tg in congenic lines with ALR, NOD.Rag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines. We hypothesize that the background differences are due to disease-modifying genes. Identification of modifier genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered. Most importantly, identified modifier genes provide new targets for the development of therapies.

Key words::

• Amyotrophic lateral sclerosis
• genetic background
• genetic modifiers

Acknowledgements

The authors wish to thank David Schroeder for general laboratory practices and colony maintenance. We also thank Denise Figlewicz for her comments and shared data. The collaboration and meetings of the authors was supported by the ALS Hope Foundation.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.