TY  - JOUR
AU  - Guillot, Simon J
AU  - Lang, Christina
AU  - Simonot, Marie
AU  - Beckett, Daniel
AU  - Lulé, Dorothée
AU  - Balz, Luisa T
AU  - Knehr, Antje
AU  - Stuart-Lopez, Geoffrey
AU  - Vercruysse, Pauline
AU  - Dieterlé, Stéphane
AU  - Weydt, Patrick
AU  - Dorst, Johannes
AU  - Kandler, Katharina
AU  - Kassubek, Jan
AU  - Wassermann, Laura
AU  - Rouaux, Caroline
AU  - Arthaud, Sébastien
AU  - Da Cruz, Sandrine
AU  - Luppi, Pierre-Hervé
AU  - Roselli, Francesco
AU  - Ludolph, Albert C
AU  - Dupuis, Luc
AU  - Bolborea, Matei
TI  - Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.
JO  - Science translational medicine
VL  - 17
IS  - 783
SN  - 1946-6234
CY  - Washington, DC
PB  - AAAS
M1  - DZNE-2025-00283
SP  - eadm7580
PY  - 2025
AB  - 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 (Sod1G86R, FusΔNLS/+, and TDP43Q331K). 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 Sod1G86R 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.
KW  - Animals
KW  - Amyotrophic Lateral Sclerosis: drug therapy
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Orexins: metabolism
KW  - Disease Models, Animal
KW  - Humans
KW  - Sleep: drug effects
KW  - Male
KW  - Melanins: metabolism
KW  - Mice
KW  - Wakefulness: drug effects
KW  - Female
KW  - Motor Neurons: drug effects
KW  - Motor Neurons: pathology
KW  - Motor Neurons: metabolism
KW  - Hypothalamic Hormones: metabolism
KW  - Pituitary Hormones: metabolism
KW  - Orexin Receptors: metabolism
KW  - Superoxide Dismutase-1: metabolism
KW  - Superoxide Dismutase-1: genetics
KW  - Mice, Transgenic
KW  - Orexins (NLM Chemicals)
KW  - Melanins (NLM Chemicals)
KW  - melanin-concentrating hormone (NLM Chemicals)
KW  - Hypothalamic Hormones (NLM Chemicals)
KW  - Pituitary Hormones (NLM Chemicals)
KW  - Orexin Receptors (NLM Chemicals)
KW  - Superoxide Dismutase-1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39879320
DO  - DOI:10.1126/scitranslmed.adm7580
UR  - https://pub.dzne.de/record/276320
ER  -