Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, MELANIN-CONCENTRATING HORMONE, EYE-MOVEMENT SLEEP, INDEPENDENT COMPONENTS, MCH NEURONS, TDP-43, TESTS, EEG, ALS, IDENTIFICATION, EPIDEMIOLOGY, Animals, Amyotrophic Lateral Sclerosis, Disease Models, Animal, Humans, Orexins, Mice, Sleep, Male, Orexin Receptor Antagonists, Female, Melanins, Pituitary Hormones, Hypothalamic Hormones, Motor Neurons, Wakefulness, Mice, Transgenic, Middle Aged, Sleep Wake Disorders, Polysomnography, 06 Biological Sciences, 11 Medical and Health Sciences, 3206 Medical biotechnology, 4003 Biomedical engineering

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.