Modeling Motor Neuron Resilience in ALS Using Stem Cells

Abstract

Summary: Oculomotor neurons, which regulate eye movement, are resilient to degeneration in the lethal motor neuron disease amyotrophic lateral sclerosis (ALS). It would be highly advantageous if motor neuron resilience could be modeled in vitro. Toward this goal, we generated a high proportion of oculomotor neurons from mouse embryonic stem cells through temporal overexpression of PHOX2A in neuronal progenitors. We demonstrate, using electrophysiology, immunocytochemistry, and RNA sequencing, that in vitro-generated neurons are bona fide oculomotor neurons based on their cellular properties and similarity to their in vivo counterpart in rodent and man. We also show that in vitro-generated oculomotor neurons display a robust activation of survival-promoting Akt signaling and are more resilient to the ALS-like toxicity of kainic acid than spinal motor neurons. Thus, we can generate bona fide oculomotor neurons in vitro that display a resilience similar to that seen in vivo. : Motor neuron subpopulations show differential vulnerability to degeneration in ALS. Allodi and colleagues report the generation of bona fide oculomotor neurons from stem cells. Similar to their in vivo counterparts, in vitro-derived oculomotor neurons, which showed a high level of protective Akt signaling, were resistant to ALS-like toxicity. Thus, they provide a novel in vitro model for motor neuron resilience in ALS. Keywords: stem cells, Phox2a, oculomotor neurons, spinal motor neurons, RNA sequencing, LCM sequencing, amyotrophic lateral sclerosis, ALS, neuronal vulnerability and resistance, Onuf’s nucleus