Sleep alterations in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease inexorably leading to premature death. Sleep disturbances have

been ascribed to respiratory insufficiency, muscle cramps, spasticity, or restless legs syndrome, all leading to increased wakefulness. However, a recent

neuropathological study in ALS patients described a loss of orexin-producing neurons, a neuropeptide involved in sleep and metabolic regulation,

undermining the idea that sleep alterations are linked to central and peripheral changes. Yet, sleep alterations are poorly characterized in ALS, and their

relationships to motor symptom onset, disease progression and orexin neurons remain unknown. Here, we performed a translational investigation using

polysomnography in patients and presymptomatic gene carriers of ALS. We also translated our findings into two mouse models of ALS and performed a

rescue using a pharmacological tool. For the first time, in both ALS patients and presymptomatic gene carriers, polysomnography revealed increased

wakefulness and a significant decrease in the non-rapid eye movement phase (NREM). Proving that sleep alterations are present in ALS and are indeed

predating symptoms onset. The same observations were made in our mouse models. Moreover, when administering Suvorexant, a drug antagonizing orexin

receptors, to our mouse models, it rescued these sleep alterations by decreasing wakefulness and increasing NREM bouts. This translational investigation

highlights the importance of such sleep alterations in the disease’s progression and its clinical relevance in ALS, paving the way to the potential use of

Suvorexant in the clinic.