Modelling amyotrophic lateral sclerosis in mice

P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis

“…A family history is present in 5-10% of patients of ALS (familial ALS or fALS). The first mutations reported were those in the gene coding for Cu/Zn superoxide dismutase (SOD1) protein, which account for around 15% of all fALS and 1-2% of the sporadic cases (sporadic ALS or sALS) in European population (Rosen et al, 1993;Stephenson and Amor, 2017;Zou et al, 2017). Interestingly, these mutations (nearly 200 different mutations have been reported) do not impair the enzymatic activity of SOD1.…”

“…Ideally, mouse models should present all the hallmarks of the human disease, namely, MN loss, muscle weakness and atrophy, metabolic deficits, TDP-43 inclusions and proteinopathy, gliosis, and changes in innate immunity. Even though available models are far from being perfect, they have been useful to understand ALS pathogenesis, to identify new drug targets with therapeutic potential, as well as to establish the proof of concept of the efficacy and safety of lead compounds (Stephenson and Amor, 2017). This is particularly true for the SOD1 G93A mice that is by far the model that has been, and it is being used more frequently.…”

“…The discovery of new genes linked to ALS (Chia et al, 2018) and the fast development of gene editing techniques such as CRISPR/Cas9 will surely increase the number of ALS mouse models, giving rise to a drug testing platform that includes the high variability of the human disease. We describe below the models that are more frequently used, emphasizing their advantages and caveats for drug discovery, previously described in two detailed recent reviews (Stephenson and Amor, 2017;Lutz, 2018).…”

“…As mutations in SOD1 are found in a minority of ALS cases, the model is not representative of the whole patient population. This is of great importance, as SOD1 mutations do not result in TDP-43 inclusions in the SOD1 G93A model, with this hallmark of disease pathogenesis being not commonly present in either SOD1 patients or mice (Stephenson and Amor, 2017). However, other SOD1 models such as SOD1 G86S do exhibit TDP-43 inclusions and could be used to overcome this pitfall (Jeon et al, 2019).…”

Cell-based Research and Therapy for Amyotrophic Lateral Sclerosis: Promises and Challenges

“…Preclinical studies of MSC therapy for ALS are primarily based on transgenic mice and rats with SOD1 mutations. Despite being a model that genetically represents only a small portion of ALS patients, it recapitulates critical hallmarks of motoneuron degeneration such as axonal degeneration, apoptosis, and accentuated gliosis (17). These studies vary in their therapeutic approach, testing different MSCs sources, allogenic or xenogeneic origin, therapeutic window, administration routes and dosages.…”