Rowe Rachel K, Schulz Philip, He Ping, Mannino Grant S, Opp Mark R, Sierks Michael R
Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, United States.
Chemical Engineering, The School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ, United States.
Front Neurosci. 2024 Jul 24;18:1436966. doi: 10.3389/fnins.2024.1436966. eCollection 2024.
Insufficient or disturbed sleep is strongly associated with adverse health conditions, including various neurodegenerative disorders. While the relationship between sleep and neurodegenerative disease is likely bidirectional, sleep disturbances often predate the onset of other hallmark clinical symptoms. Neuronal waste clearance is significantly more efficient during sleep; thus, disturbed sleep may lead to the accumulation of neuronal proteins that underlie neurodegenerative diseases. Key pathological features of neurodegenerative diseases include an accumulation of misfolded or misprocessed variants of amyloid beta (Aβ), tau, alpha synuclein (α-syn), and TarDNA binding protein 43 (TDP-43). While the presence of fibrillar protein aggregates of these neuronal proteins are characteristic of neurodegenerative diseases, the presence of small soluble toxic oligomeric variants of these different proteins likely precedes the formation of the hallmark aggregates.
We hypothesized that sleep deprivation would lead to accumulation of toxic oligomeric variants of Aβ, tau, α-syn, and TDP-43 in brain tissue of wild-type mice. Adult mice were subjected to 6 h of sleep deprivation (zeitgeber 0-6) for 5 consecutive days or were left undisturbed as controls. Following sleep deprivation, brains were collected, and protein pathology was assessed in multiple brain regions using an immunostain panel of reagents selectively targeting neurodegenerative disease-related variants of Aβ, tau, α-syn, and TDP-43.
Overall, sleep deprivation elevated levels of all protein variants in at least one of the brain regions of interest. The reagent PDTDP, targeting a TDP-43 variant present in Parkinson's disease, was elevated throughout the brain. The cortex, caudoputamen, and corpus callosum brain regions showed the highest accumulation of pathology following sleep deprivation.
These data provide a direct mechanistic link between sleep deprivation, and the hallmark protein pathologies of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.
睡眠不足或睡眠紊乱与不良健康状况密切相关，包括各种神经退行性疾病。虽然睡眠与神经退行性疾病之间的关系可能是双向的，但睡眠障碍往往早于其他标志性临床症状的出现。睡眠期间神经元废物清除效率显著提高；因此，睡眠紊乱可能导致神经退行性疾病所基于的神经元蛋白质积累。神经退行性疾病的关键病理特征包括淀粉样β蛋白（Aβ）、tau蛋白、α-突触核蛋白（α-syn）和TarDNA结合蛋白43（TDP-43）的错误折叠或错误加工变体的积累。虽然这些神经元蛋白的纤维状蛋白聚集体的存在是神经退行性疾病的特征，但这些不同蛋白的小的可溶性毒性寡聚变体的存在可能先于标志性聚集体的形成。
我们假设睡眠剥夺会导致野生型小鼠脑组织中Aβ、tau、α-syn和TDP-43的毒性寡聚变体积累。成年小鼠连续5天接受6小时睡眠剥夺（时间geber 0-6），或作为对照不受干扰。睡眠剥夺后，收集大脑，并使用选择性靶向与神经退行性疾病相关的Aβ、tau、α-syn和TDP-43变体的试剂免疫染色面板在多个脑区评估蛋白质病理学。
总体而言，睡眠剥夺至少在一个感兴趣的脑区中提高了所有蛋白变体的水平。靶向帕金森病中存在的TDP-43变体的试剂PDTDP在整个大脑中升高。睡眠剥夺后，皮质、尾壳核和胼胝体脑区显示出最高的病理积累。
这些数据提供了睡眠剥夺与神经退行性疾病（如阿尔茨海默病和帕金森病）的标志性蛋白质病理学之间的直接机制联系。
