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@ARTICLE{Guillot:276320,
author = {Guillot, Simon J and Lang, Christina and Simonot, Marie and
Beckett, Daniel and Lulé, Dorothée and Balz, Luisa T and
Knehr, Antje and Stuart-Lopez, Geoffrey and Vercruysse,
Pauline and Dieterlé, Stéphane and Weydt, Patrick and
Dorst, Johannes and Kandler, Katharina and Kassubek, Jan and
Wassermann, Laura and Rouaux, Caroline and Arthaud,
Sébastien and Da Cruz, Sandrine and Luppi, Pierre-Hervé
and Roselli, Francesco and Ludolph, Albert C and Dupuis, Luc
and Bolborea, Matei},
title = {{E}arly-onset sleep alterations found in patients with
amyotrophic lateral sclerosis are ameliorated by orexin
antagonist in mouse models.},
journal = {Science translational medicine},
volume = {17},
number = {783},
issn = {1946-6234},
address = {Washington, DC},
publisher = {AAAS},
reportid = {DZNE-2025-00283},
pages = {eadm7580},
year = {2025},
abstract = {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.},
keywords = {Animals / Amyotrophic Lateral Sclerosis: drug therapy /
Amyotrophic Lateral Sclerosis: pathology / Amyotrophic
Lateral Sclerosis: metabolism / Orexins: metabolism /
Disease Models, Animal / Humans / Sleep: drug effects / Male
/ Melanins: metabolism / Mice / Wakefulness: drug effects /
Female / Motor Neurons: drug effects / Motor Neurons:
pathology / Motor Neurons: metabolism / Hypothalamic
Hormones: metabolism / Pituitary Hormones: metabolism /
Orexin Receptors: metabolism / Superoxide Dismutase-1:
metabolism / Superoxide Dismutase-1: genetics / Mice,
Transgenic / Orexins (NLM Chemicals) / Melanins (NLM
Chemicals) / melanin-concentrating hormone (NLM Chemicals) /
Hypothalamic Hormones (NLM Chemicals) / Pituitary Hormones
(NLM Chemicals) / Orexin Receptors (NLM Chemicals) /
Superoxide Dismutase-1 (NLM Chemicals)},
cin = {Clinical Study Center (Ulm) / AG Roselli},
ddc = {500},
cid = {I:(DE-2719)5000077 / I:(DE-2719)1910001},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 352 -
Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39879320},
doi = {10.1126/scitranslmed.adm7580},
url = {https://pub.dzne.de/record/276320},
}