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α-Synuclein Induced the Occurrence of RBD via Interaction with OX1R and Modulated Its Degradation

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Abstract

Rapid eye movement (REM) sleep behavior disorder (RBD) is a powerful early sign of Parkinson’s disease (PD), but the pathogenetic mechanism involved in RBD remains largely unexplored. α-Synuclein has been verified to form Lewy bodies in the orexin neurons, whose activity and function rely on the orexin 1 receptor (OX1R). Dysfunction of the OX1R may induce the occurrence of RBD. Here, we determined the role of the interaction between α-Synuclein and OX1R in the pathogenesis of RBD, in vitro and in vivo. We found that injection of α-Synuclein into the lateral hypothalamus area (LHA) damaged orexin neurons and induced the RBD-like sleep pattern, to further damage dopaminergic neurons and result in locomotor dysfunction in mice. α-Synuclein interacted with OX1R, promoting the degradation of OX1R through proteasomal and lysosomal pathways. In addition, overexpression of α-Synuclein downregulated OX1R-mediated signaling, subsequently leading to orexin neuron damage. We conclude that α-Synuclein induced the occurrence of RBD via interaction with OX1R and modulated its degradation. These findings provide evidence for a novel mechanism by which the association of α-Synuclein with OX1R was attributed to α-Synuclein-induced orexin neuron damage, which may be a new molecular target for an effective therapeutic strategy for RBD pathology.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank International Science Editing ( http://www.internationalscienceediting.com ) for editing this manuscript.

Funding

This study was supported by the National Natural Science Foundation of the People’s Republic of China (81972231).

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  1. Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100069, China

    Jing Kai Fan, Meng Chen Wang, Hui Min Yang, Jian Nan Zhang, Li Gu & Hong Zhang

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  1. Jing Kai Fan
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Contributions

HZ and LG conceived and designed research. JKF and MCW conducted experiments. JKF, MCW, and LG analyzed data. HZ and LG wrote the manuscript; HMY and JNZ revised the manuscript. HZ acquired the funding and financial support for the project. All authors read and approved the manuscript for publication.

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Correspondence to Li Gu or Hong Zhang.

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This study was reviewed and approved by the ethics committee of Capital Medical University (2019SY040). Written informed consent from all subjects was obtained. All animals experiments protocols were approved by the Committee on Animal Care and Usage of Capital Medical University (AEEI-2020-141).

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Fan, J.K., Wang, M.C., Yang, H.M. et al. α-Synuclein Induced the Occurrence of RBD via Interaction with OX1R and Modulated Its Degradation. Neuromol Med 25, 286–300 (2023). https://doi.org/10.1007/s12017-023-08735-4

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