Sleep disturbances, including rapid eye movement sleep behavior disorder (RBD), excessive daytime sleepiness, and insomnia, are common non-motor manifestations of Parkinson’s disease (PD). Little is known about the underlying mechanisms, partly due to the inability of current rodent models to adequately mimic the human PD sleep phenotype. Clinically, increasing studies have reported that variants of the glucocerebrosidase gene (GBA) increase the risk of PD. Here, we developed a mouse model characterized by sleep–wakefulness by injecting α-synuclein preformed fibronectin (PFF) into the sublaterodorsal tegmental nucleus (SLD) of GBA L444P mutant mice and investigated the role of the GBA L444P variant in the transition from rapid eye movement sleep behavior disorder to PD. Initially, we analyzed spectral correlates of REM and NREM sleep in GBA L444P mutant mice. Importantly, EEG power spectral analysis revealed that GBA L444P mutation mice exhibited reduced delta power during non-rapid eye movement (NREM) sleep and increased theta power (8.2–10 Hz) in active rapid eye movement (REM) sleep phases. Our study revealed that GBA L444P-mutant mice, after receiving PFF injections, exhibited increased sleep fragmentation, significant motor and cognitive dysfunctions, and loss of dopaminergic neurons in the substantia nigra. Furthermore, the over-expression of GBA-AAV partially improved these sleep disturbances and motor and cognitive impairments. In conclusion, we present the initial evidence that the GBA L444P mutant mouse serves as an essential tool in understanding the complex sleep disturbances associated with PD. This model further provides insights into potential therapeutic approaches, particularly concerning α-synuclein accumulation and its subsequent pathological consequences.

睡眠障碍，包括快速动眼睡眠行为障碍 (RBD)、白天过度嗜睡和失眠，是帕金森病 (PD) 的常见非运动表现。人们对潜在的机制知之甚少，部分原因是目前的啮齿动物模型无法充分模拟人类 PD 睡眠表型。临床上，越来越多的研究表明，葡萄糖脑苷脂酶基因 ( GBA ) 的变异会增加患 PD 的风险。在这里，我们通过将α-突触核蛋白预制纤连蛋白（PFF）注射到GBA L444P突变小鼠的背背下被盖核（SLD）中，开发了一种以睡眠-觉醒为特征的小鼠模型，并研究了GBA L444P变体在快速眼转变中的作用运动睡眠行为障碍至PD。最初，我们分析了GBA L444P 突变小鼠的 REM 和 NREM 睡眠的光谱相关性。重要的是，EEG 功率谱分析显示， GBA L444P 突变小鼠在非快速眼动 (NREM) 睡眠期间表现出 delta 功率降低，而在活跃快速眼动 (REM) 睡眠阶段表现出 theta 功率 (8.2–10 Hz) 增加。我们的研究表明， GBA L444P 突变小鼠在接受 PFF 注射后，表现出睡眠碎片化增加、显着的运动和认知功能障碍以及黑质中多巴胺能神经元的丧失。此外， GBA -AAV 的过度表达部分改善了这些睡眠障碍以及运动和认知障碍。总之，我们提出了初步证据，表明GBA L444P 突变小鼠是理解与 PD 相关的复杂睡眠障碍的重要工具。 该模型进一步提供了对潜在治疗方法的见解，特别是关于 α-突触核蛋白积累及其随后的病理后果。