New Model to Study ALS-Resilient Neurons

Researchers at Karolinska Institutet in Sweden have developed a stem cell–based model in order to study the resilience and vulnerability of neurons in the neurodegenerative disease Amyotrophic lateral sclerosis (ALS). The results are published in the journal Stem Cell Reports and can aid in the identification of new genetic targets for treatments protecting sensitive neurons.

ALS is a fatal disease with no effective treatment or cure. The disease is characterized by a loss of neurons controlling voluntary muscles, known as motor neurons. This causes muscle atrophy, weakness, and eventually paralysis. However, some groups of motor neurons are highly resilient and can survive all stages of the disease. These include the neurons that control our eye movements: the oculomotor neurons. Exactly why these motor neurons can withstand the disease is currently unknown.

The oculomotor neurons are found in the brain stem and are difficult to study in humans and animals. In order to further investigate the differences in sensitivity between different motor neurons, it would thus be advantageous if cultivated stem cells could be used. The researchers have now developed one such stem cell–based model of neuron resilience in ALS.

“This cell culture system can help identify new genes contributing to the resilience in oculomotor neurons that could be used in gene therapy to strengthen sensitive motor neurons,” explains senior author Eva Hedlund.

To create their model, the researchers overexpressed the transcription factor PHOX2A, which is necessary for the formation of oculomotor neurons during an embryo’s development. By performing various analyses of the cells, the researchers found many similarities between these lab-grown cells and their equivalents in mice and humans, and they conclude that the cells generated are indeed oculomotor neurons.

The researchers show that these resilient neurons that were generated from stem cells activate a survival-enhancing signal known as Akt, a signal that is also activated in oculomotor neurons in humans. The lab-generated neurons also appeared more resilient to ALS-like degeneration when compared to spinal cord motor neurons, something that is also seen in humans.

“All in all, this shows that we have created a robust model for studying mechanisms for neuron resilience and vulnerability in ALS,” says first author Ilary Allodi.