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Altered Motor Performance, Sleep EEG, and Parkinson’s Disease Pathology Induced by Chronic Sleep Deprivation in Lrrk2G2019S Mice

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Abstract

Parkinson’s disease (PD) is a multifaceted disease in which environmental variables combined with genetic predisposition cause dopaminergic (DAergic) neuron loss in the substantia nigra pars compacta. The mutation of leucine-rich repeat kinase 2 (Lrrk2) is the most common autosomal dominant mutation in PD, and it has also been reported in sporadic cases. A growing body of research suggests that circadian rhythm disruption, particularly sleep-wake abnormality, is common during the early phase of PD. Our present study aimed to evaluate the impact of sleep deprivation (SD) on motor ability, sleep performance, and PD pathologies in Lrrk2G2019S transgenic mice. After two months of SD, Lrrk2G2019S mice at 12 months of age showed an exacerbated PD-like phenotype with motor deficits, a reduced striatal DA level, degenerated DAergic neurons, and altered sleep structure and biological rhythm accompanied by the decreased protein expression level of circadian locomotor output cycles kaput Lrrk2 gene in the brain. All these changes persisted and were even more evident in 18-month-old mice after 6 months of follow-up. Moreover, a significant increase in α-synuclein aggregation was found in SD-treated transgenic mice at 18 months of age. Taken together, our findings indicate that sleep abnormalities, as a risk factor, may contribute to the pathogenesis and progression of PD. Early detection of sleep disorders and improvement of sleep quality may help to delay disease progression and provide long-term clinical benefits.

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Acknowledgments

We thank Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, and Dalian Medical University for the research infrastructure and support. This work was supported by the National Natural Science Foundation of China (81771521).

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Authors and Affiliations

  1. Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China

    Xinyao Liu, Yuanyuan Wang, Song Li, Cheng Cheng, Murad Al-Nusaif & Weidong Le

  2. Institute of Neurology, Sichuan Academy of Sciences-Sichuan Provincial Hospital of UESTC Medical School, Chengdu, 610031, China

    Hang Yu & Weidong Le

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  1. Xinyao Liu
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Correspondence to Weidong Le.

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Liu, X., Yu, H., Wang, Y. et al. Altered Motor Performance, Sleep EEG, and Parkinson’s Disease Pathology Induced by Chronic Sleep Deprivation in Lrrk2G2019S Mice. Neurosci. Bull. 38, 1170–1182 (2022). https://doi.org/10.1007/s12264-022-00881-2

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