Therapeutic targets found to design treatment for SMA

April 2017: Prof Tom Gillingwater and colleagues elucidate protection of motor neurons in the zebrafish model.

Motor neurons (the nerve cells that connect the spinal cord to the muscles of the body) break down in the motor neuron disease known as Spinal Muscular Atrophy (SMA). One striking, and up until now puzzling, feature of SMA is that not all motor neurons are equally affected. This means that, in the same patient, some motor neurons will die whereas other motor neurons are resistant to the disease. We therefore set out to identify features of motor neurons that make them either resistant or susceptible to disease in SMA.

We performed experiments, initially using mouse models, where we uncovered sets of genes that are differently expressed between resistant and susceptible motor neurons. We found that the main difference between the two types of neuron was that levels of genes involved in regulating energy production within cells were increased in motor neurons that were resistant to the disease. This suggests that the ability to generate and handle energy at the cellular level is key in determining the fate of individual motor neurons in SMA. We went on to show that manipulating these energy producing pathways, either using genetic approaches or drugs that target the pathways, protected motor neurons from disease in a zebrafish model of SMA.

By revealing key factors that make motor neurons resistant to disease in SMA, and identifying a drug that can safely and effectively target these factors to lessen the impact of disease, we now have new therapeutic targets that can be used to design treatments for SMA. There is also the possibility that this approach could be applicable to other related disorders, such as amyotrophic lateral sclerosis (ALS).


Related links

Publication in PLOS Genetics

Prof Tom Gillingwater's research profile