Role of stearoyl-coenzyme A desaturase 1, a monounsaturated fatty acid synthesis enzyme, in a transgenic model of Amyotrophic Lateral Sclerosis.

Summary Amyotrophic lateral sclerosis is a neurodegenerative disease associated with metabolic dysfunction. Alterations in lipid metabolism, described in ALS patients and animal models, could participate in the early stages of the disease. The objective of this thesis was to study the role of stearoyl-coenzyme A desaturase 1 (SCD1), a key enzyme in lipid metabolism, in ALS. By studying the peripheral fatty acid profile in an ALS mouse model, the SOD1m mice, we saw a decrease in SCD1 activity as early as the early (subclinical) stages of the disease. This decrease alone could explain the alterations in lipid metabolism characteristic of ALS. The impact of the loss of SCD1 activity on the motor axis has been studied. Gene deletion or pharmacological inhibition of SCD1 improves functional recovery after sciatic nerve injury in wild-type mice. We investigated whether the loss of SCD1 activity found in SOD1m mice is a protective mechanism against ALS progression. We treated SOD1m mice with an inhibitor of SCD1 activity. The treatment led to an increase in oxidative metabolism, preservation of neuromuscular integrity and improved motor neuron survival. We conclude that SCD1 inhibition represents a promising therapeutic target in ALS.