Lessons learnt from a new C9orf72 mouse model of ALS

Summary by Amy Keerie PhD student, the University of Sheffield
February 2021

Original articles

Lessons learnt from a new C9orf72 mouse model of ALS survival and motor phenotypes in FVB C9-500 ALS/FTD BAC transgenic mice. Reproduced by multiple labs:

Nguyen et al. 2020: https://doi.org/10.1016/j.neuron.2020.09.009

Liu et al. 2016: http://dx.doi.org/10.1016/j.neuron.2016.04.005

Mordes et al. 2020: https://doi.org/10.1016/j.neuron.2020.08.009

Lay summary

Animal models are important in scientific research as they allow us to better understand diseases and enable testing of potential therapeutic drugs. Mouse models are usually based on genetic changes found in humans who have the disease. For amyotrophic lateral sclerosis (ALS), the “gold standard” mouse model is the SOD1G93A mouse model, which is based on a specific mutation in the human SOD1 gene. This was the first mouse model for ALS and is still widely used today. These mice get progressive ALS symptoms including motor neuron loss and paralysis, however, research has shown that that drugs which show positive results in these mice often fail to translate to humans when they are taken to clinical trials. The cause of this discrepancy could be due to a variety of reasons, such as how the studies in mice were conducted. However, SOD1 mutations only account for a small proportion of ALS cases, so this original mouse model may only be representative of SOD1-specific ALS. As more ALS genes have been identified in patients over time, more animal models have been created which may better represent ALS patients, and therefore could aid with understanding the disease and finding effective treatments.

The most common genetic cause of ALS is the alteration of the C9orf72 gene and this paper discusses a mouse model that was created with a mutation of this gene. Different groups of researchers have created C9orf72 mutant mice, but only one of these (described in Liu et al., 2016) has symptoms of ALS such as motor neuron loss, paralysis and decreased lifespan compared to normal wild type (i.e. non-mutated) mice. One interesting feature of these mutant mice was that there was variability in disease severity, where some mice developed symptoms of disease rapidly, others more slowly, and others not at all. In 2017, these mice were shared with other researchers in the wider scientific community so that more research could be conducted with this model. Recently, a paper was published by Mordes et al., 2020 stating that the mice they had obtained did not show motor neuron loss, paralysis or a decreased lifespan.

The paper highlighted (Nguyen et al., 2020) is by the authors of the original 2016 paper and they back up their original findings regarding the symptoms in the mutant mice with more data from their own and from other laboratories. They suggest that differences in mouse breeding regimes, experimental design and data collection may be the reason that other research groups are not observing symptoms of ALS in the mouse model. Some of the reasons outlined for the differences seen in the symptoms are:

• Use of different background strains of mice. This can be thought of as the “ethnicity” of mice and it introduces different genetic factors that cannot be controlled for.

• The number of mice used for analysis.

• Whether the mice were split into fast and slow disease progressors for some types of analysis.

• The frequency of data collection. Sudden changes can be missed if the time points are too spread out.

• The environmental conditions in each laboratory. Things like the food given, pH of water and bacteria present may affect the mice.

All of these factors need to be investigated further. This debate about how accurately the C9orf72 mouse models ALS is really important and highlights some of the limitations of using animal models for disease. Models need to be robust and reproducible, so standard protocols need to be adopted by different research laboratories around the world in order to gain a better understanding of ALS and develop treatments.

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