Finding novel treatments that protect motor neurons from degeneration remains a cornerstone of therapeutic development for motor neuron diseases such as ALS and SMA. In this talk I will present my lab’s identification of bioenergetics pathways as important, endogenous regulators of motor neuron stability in vivo. I will discuss how activation of PGK1 represents an attractive therapeutic in this regard, and present ongoing work to translate pre-clinical findings into clinical trials for patients with ALS.