GBA-AAV 可减轻快速眼动睡眠行为障碍小鼠的睡眠紊乱和运动障碍。

IF 6.7 1区 医学 Q1 NEUROSCIENCES
Ying Chen, Wei-Ye Xie, Dong Xia, Mu-Tian Zhang, Yan-Rui Sun, Wen-Xiang Duan, Yun Shen, Fen Wang, Wei-Min Qu, Zhi-Li Huang, Chun-Feng Liu
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引用次数: 0

摘要

睡眠障碍,包括快速眼动睡眠行为障碍(RBD)、白天过度嗜睡和失眠,是帕金森病(PD)常见的非运动表现。人们对其潜在机制知之甚少,部分原因是目前的啮齿类动物模型无法充分模拟人类帕金森病的睡眠表型。临床上,越来越多的研究报告称葡萄糖脑苷脂酶基因(GBA)变异会增加罹患帕金森病的风险。在此,我们通过将α-突触核蛋白预成纤维蛋白(PFF)注射到GBA L444P变异小鼠的侧脑室下被盖核(SLD)中,建立了一种以睡眠觉醒为特征的小鼠模型,并研究了GBA L444P变异在快速眼动睡眠行为障碍向帕金森病转变过程中的作用。首先,我们分析了 GBA L444P 突变小鼠快速眼动和非快速眼动睡眠的频谱相关性。重要的是,脑电图功率频谱分析表明,GBA L444P 突变小鼠在非快速眼动(NREM)睡眠阶段表现出较低的 delta 功率,而在活跃的快速眼动(REM)睡眠阶段则表现出较高的 theta 功率(8.2-10 Hz)。我们的研究发现,GBA L444P 突变小鼠在接受 PFF 注射后,表现出睡眠片段增多、明显的运动和认知功能障碍以及黑质多巴胺能神经元的缺失。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,我们提出的初步证据表明,GBA L444P 突变小鼠是了解与帕金森病相关的复杂睡眠障碍的重要工具。该模型进一步为潜在的治疗方法提供了见解,尤其是关于α-突触核蛋白的积累及其随后的病理后果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

GBA-AAV mitigates sleep disruptions and motor deficits in mice with REM sleep behavior disorder.

GBA-AAV mitigates sleep disruptions and motor deficits in mice with REM sleep behavior disorder.

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.

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来源期刊
NPJ Parkinson's Disease
NPJ Parkinson's Disease Medicine-Neurology (clinical)
CiteScore
9.80
自引率
5.70%
发文量
156
审稿时长
11 weeks
期刊介绍: npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
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