Experimental models of motor neuron disease Reliable tools are necessary to understand the aetiology of neurodegenerative disorders. Towards this goal, European scientists developed new models for amyotrophic lateral sclerosis (ALS) to study the underlying mechanisms leading to neuronal death. Health © molekuul_be, Shutterstock ALS is a fatal neurodegenerative disease characterised by death of motor neurons. Patients die within 2-5 years from diagnosis due to failure of the breathing muscles. The first mutation associated with familial ALS was localised in the superoxide dismutase 1 (SOD1) gene that is involved in the destruction of free radicals. Subsequent studies on animal models carrying the human mutant gene indicated that many different cell types contribute to the pathologic mechanisms of ALS. Recent evidence underscores a role for glia, the cells supporting the neurons in the brain and spinal cord, in disease development and progression. Studies with induced neural progenitor cells (iNPCs) from ALS patients have modelled both sporadic and familial forms of the disease and demonstrated the toxic effect of astrocytes. The EU-funded TOXICITY IN MND (Screening of candidate targets for astrocytic toxicity in motor neurone disease) project wished to identify the factors that contribute to this astrocyte-mediated toxicity. The ultimate goal was to use gene therapy approaches to silence these toxic genes and improve neuronal activity and survival. In this context, researchers performed gene expression analysis of astrocytes from the ALS mouse model and identified several candidate genes and pathways potentially involved in astrocyte toxicity. Particular emphasis was given to genes belonging to or regulating the complement system, inflammation and the immune responses by glia. From a therapeutic perspective, the consortium screened 1 200 drugs to identify chemical compounds that decreased glia toxicity and rescued neuronal survival. They discovered 17 compounds that were more effective in protecting neurons than the only FDA approved drug used on ALS patients, i.e. Riluzole. Additionally, they employed a gene therapy approach to silence SOD1 in the animal model of the disease at different time points. The researchers also proved the efficacy and safety of this approach in non-human primates. Overall, the TOXICITY IN MND project has successfully developed a number of new in vitro models of both the sporadic and the genetic form of ALS. Using these tools, future studies will provide a unique opportunity to extend the screening of drugs and open avenues towards personalised treatments. Keywords Model, motor neuron, amyotrophic lateral sclerosis, SOD1, glia, astrocyte, gene therapy, drug
