Journal Article

DZNE-2025-00283

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.

Guillot, S. J. ; Lang, C.DZNE* ; Simonot, M. ; Beckett, D. ; Lulé, D.DZNE* ; Balz, L. T.DZNE* ; Knehr, A.DZNE* ; Stuart-Lopez, G. ; Vercruysse, P. ; Dieterlé, S. ; Weydt, P.DZNE* ; Dorst, J.DZNE* ; Kandler, K.DZNE* ; Kassubek, J.DZNE* ; Wassermann, L. ; Rouaux, C. ; Arthaud, S. ; Da Cruz, S. ; Luppi, P.-H. ; Roselli, F.DZNE* ; Ludolph, A. C.DZNE* ; Dupuis, L. ; Bolborea, M.

2025
AAAS Washington, DC

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Please use a persistent id in citations: doi:10.1126/scitranslmed.adm7580

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.

Keyword(s): Animals (MeSH) ; Amyotrophic Lateral Sclerosis: drug therapy (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Orexins: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Humans (MeSH) ; Sleep: drug effects (MeSH) ; Male (MeSH) ; Melanins: metabolism (MeSH) ; Mice (MeSH) ; Wakefulness: drug effects (MeSH) ; Female (MeSH) ; Motor Neurons: drug effects (MeSH) ; Motor Neurons: pathology (MeSH) ; Motor Neurons: metabolism (MeSH) ; Hypothalamic Hormones: metabolism (MeSH) ; Pituitary Hormones: metabolism (MeSH) ; Orexin Receptors: metabolism (MeSH) ; Superoxide Dismutase-1: metabolism (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; Mice, Transgenic (MeSH) ; Orexins ; Melanins ; melanin-concentrating hormone ; Hypothalamic Hormones ; Pituitary Hormones ; Orexin Receptors ; Superoxide Dismutase-1

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Contributing Institute(s):

1. Clinical Study Center (Ulm) (Clinical Study Center (Ulm))
2. Metabolic Changes in Neurodegeneration (AG Roselli)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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