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Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models

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Jan 25, 2025 version files 66.35 KB

Abstract

Lateral hypothalamic neurons producing melanin-concentrating hormone (MCH) and orexin/hypocretin are involved in sleep regulation. Both MCH and orexin neurons are altered in amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease. However, sleep alterations are currently poorly characterized in ALS, and could represent either early symptoms or late consequences of disease progression. We characterized sleep architecture using polysomnography in cohorts of both early ALS patients without respiratory impairment and presymptomatic carriers of mutations leading to familial ALS. We observed sleep alterations, including increased wake and decreased deep sleep (non-rapid eye movement—NREM3) and increased wake correlated with worse cognitive performance, in particular, verbal fluency in both cohorts. These changes in sleep architecture were replicated in three mouse models of familial ALS, Sod1G86R, FusΔNLS/+ and TDP-43Q331K mice. Altered sleep structure in mice was fully rescued by per os administration of a dual-orexin receptor antagonist, and partially rescued by intracerebroventricular MCH.