Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models
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 <i>C9ORF72</i> and <i>SOD1</i> 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 (<i>Sod1<sup>G86R</sup></i>, <i>Fus</i><sup>Δ<i>NLS/+</i></sup>, and <i>TDP43<sup>Q331K</sup></i>). 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 <i>Sod1<sup>G86R</sup></i> 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.
Authors
- Albert C. Ludolph (ORCID: https://orcid.org/0000-0002-5401-0904)
- Patrick Weydt (ORCID: https://orcid.org/0000-0003-2344-5662)
- Christina Lang (ORCID: https://orcid.org/0000-0002-2953-7157)
- Matei Bolborea (ORCID: https://orcid.org/0000-0003-2313-2770)
- Luc Dupuis (ORCID: https://orcid.org/0000-0002-0902-5824)
- Pierre‐Hervé Luppi (ORCID: https://orcid.org/0000-0002-0503-423X)
- Caroline Rouaux (ORCID: https://orcid.org/0000-0002-5724-2903)
- Sébastien Arthaud (ORCID: https://orcid.org/0000-0001-7271-5468)
- David Beckett
- Francesco Roselli (ORCID: https://orcid.org/0000-0001-9935-6899)
- Stéphane Dieterle
- Laura Wassermann (ORCID: https://orcid.org/0009-0004-4057-2975)
- Simon J. Guillot (ORCID: https://orcid.org/0000-0002-1623-7091)
- Sandrine Da Cruz (ORCID: https://orcid.org/0000-0003-1986-4565)
- Katharina Kandler (ORCID: https://orcid.org/0000-0002-0785-379X)
- Johannes Dorst (ORCID: https://orcid.org/0000-0001-6352-0909)
- Antje Knehr
- Dorothée Lulé (ORCID: https://orcid.org/0000-0001-5944-398X)
- Jan Kassubek (ORCID: https://orcid.org/0000-0002-7106-9270)
- Marie Simonot
- Pauline Vercruysse
- Geoffrey Stuart‐Lopez (ORCID: https://orcid.org/0009-0009-0074-3019)
- Luisa T. Balz (ORCID: https://orcid.org/0009-0002-8088-3386)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- German Center for Neurodegenerative Diseases (DE)
- Centre de Recherche en Neurosciences de Lyon (FR)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- University Hospital Ulm (DE)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-01-29
- DOI
- https://doi.org/10.1126/scitranslmed.adm7580
- Citations
- 21
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 29.17