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

• DOI: 10.1126/scitranslmed.adm7580
• Publication Date: 2025-01-29T18:58:33Z
• Authors: Simon J. Guillot; Christina Lang; Marie Simonot; Daniel Beckett; Dorothée Lulé; Luisa T. Balz; Antje Knehr; Geoffrey Stuart-L...; Pauline Vercruysse; Stéphane Dieterlé; Patrick Weydt; Johannes Dorst; Katharina Kandler; Jan Kassubek; Laura Wassermann; Caroline Rouaux; Sébastien Arthaud; Sandrine Da Cruz; Pierre-Hervé Luppi; Francesco Roselli; Albert C. Ludolph; Luc Dupuis; Matei Bolborea
• Keywords: Male; pathology [Motor Neurons]; metabolism [Orexins]; Mice, Transgenic; Mice; Superoxide Dismutase-1; metabolism [Pituitary Hormones]; Orexin Receptors; Animals; Humans; pathology [Amyotrophic Lateral Sclerosis]; drug effects [Motor Neurons]; metabolism [Orexin Receptors]; Melanins; metabolism [Superoxide Dismutase-1]; Orexins; Hypothalamic Hormones; drug therapy [Amyotrophic Lateral Sclerosis]; metabolism [Amyotrophic Lateral Sclerosis]; drug effects [Sleep]; metabolism [Motor Neurons]; melanin-concentrating hormone; metabolism [Melanins]; genetics [Superoxide Dismutase-1]; Disease Models, Animal; Pituitary Hormones; drug effects [Wakefulness]; Female; ddc:500; metabolism [Hypothalamic Hormones]

Sleep alterations have been described in several neurodegenerative diseases yet are currently poorly characterized in amyotrophic lateral sclerosis (ALS). This study investigates sleep macroarchitecture and related hypothalamic signaling disruptions in ALS. Using polysomnography, we found that both patients with ALS as well as asymptomatic C9ORF72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non–rapid eye movement sleep. Increased wakefulness correlated with diminished cognitive performance in both clinical cohorts. Similar changes in sleep macroarchitecture were observed in three ALS mouse models (

Sod1 G86R

, Fus

Δ NLS/+

, and

TDP43 Q331K

). A single oral administration of a dual-orexin receptor antagonist or intracerebroventricular delivery of melanin-concentrating hormone (MCH) through an osmotic pump over 15 days partially normalized sleep patterns in mouse models. MCH treatment did not extend the survival of

Sod1 G86R

mice but did decrease the loss of lumbar motor neurons. These findings suggest MCH and orexin signaling as potential targets to treat sleep alterations that arise in early stages of the disease.