Guillot Simon J, Lang Christina, Simonot Marie, Beckett Daniel, Lulé Dorothée, Balz Luisa T, Knehr Antje, Stuart-Lopez Geoffrey, Vercruysse Pauline, Dieterlé Stéphane, Weydt Patrick, Dorst Johannes, Kandler Katharina, Kassubek Jan, Wassermann Laura, Rouaux Caroline, Arthaud Sébastien, Da Cruz Sandrine, Luppi Pierre-Hervé, Roselli Francesco, Ludolph Albert C, Dupuis Luc, Bolborea Matei
University of Strasbourg, INSERM, Strasbourg Translational Neuroscience & Psychiatry STEP-CRBS, UMR-S 1329, 67000 Strasbourg, France.
Department of Neurology, University Hospital of Ulm, 89081 Ulm, Germany.
Sci Transl Med. 2025 Jan 29;17(783):eadm7580. doi: 10.1126/scitranslmed.adm7580.
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 and 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 (, , and ). 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 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.
睡眠改变在几种神经退行性疾病中已有描述，但目前在肌萎缩侧索硬化症（ALS）中的特征尚不明确。本研究调查了ALS患者的睡眠宏观结构以及相关的下丘脑信号传导中断情况。通过多导睡眠图，我们发现ALS患者以及无症状突变携带者均表现出觉醒增加和非快速眼动睡眠减少。在两个临床队列中，觉醒增加均与认知能力下降相关。在三种ALS小鼠模型（、和）中也观察到了类似的睡眠宏观结构变化。单次口服双食欲素受体拮抗剂或通过渗透泵在15天内脑室内注射黑色素浓缩激素（MCH）可使小鼠模型的睡眠模式部分恢复正常。MCH治疗并未延长小鼠的生存期，但确实减少了腰段运动神经元的损失。这些发现表明，MCH和食欲素信号传导可能是治疗该疾病早期出现的睡眠改变的潜在靶点。
