{"title":"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。","authors":"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","doi":"10.1038/s41531-024-00756-5","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297138/pdf/","citationCount":"0","resultStr":"{\"title\":\"GBA-AAV mitigates sleep disruptions and motor deficits in mice with REM sleep behavior disorder.\",\"authors\":\"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\",\"doi\":\"10.1038/s41531-024-00756-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":19706,\"journal\":{\"name\":\"NPJ Parkinson's Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2024-08-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297138/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Parkinson's Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41531-024-00756-5\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Parkinson's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41531-024-00756-5","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
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.
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.