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Brain regions susceptible to alpha-synuclein spreading

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Abstract

The spreading of misfolded alpha-synuclein (α-syn) protein has been observed in animal models of Parkinson’s disease (PD) and other α-synucleinopathies that mimic human PD pathologies. In animal models, the spreading of α-syn has been associated with motor dysfunction and neuronal death. However, variability in both susceptible brain regions and cellular populations limits our understanding of the consequences of α-syn spreading and the development of associated therapies. Here, we have reviewed the physiological and pathological functions of α-syn and summarized the susceptible brain regions and cell types identified from human postmortem studies and exogenous α-syn injection-based animal models. We have reviewed the methods for inducing α-syn aggregation, the specific hosts, the inoculation sites, the routes of propagation, and other experimental settings that may affect the spreading pattern of α-syn, as reported in current studies. Understanding the spread of α-syn to produce a consistent PD animal model is vital for future drug discovery.

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Fig. 1: Schematic diagrams illustrating the neuropathological staging systems for α-synucleinopathies.
Fig. 2: The selectivity of brain areas for α-syn pathology in exogenous α-syn injection-based animal models is affected by the inoculation site and route.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82071191, 81722016, 32000724, 31800899), the China Postdoctoral Science Foundation (2019M650241, 2018M633375), the Key Research Projects of Sichuan Province (2020YFS0279, 2019YFS0212), and the Fundamental Research Funds for the Central Universities (2021SCU12103).

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  1. Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

    Yu-Jie Guo, Huan Xiong, Kang Chen, Jin-Jun Zou & Peng Lei

  2. West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, China

    Yu-Jie Guo

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YG and PL conceived the review; YG and KC performed the literature search and data analysis; YG and JZ prepared the figures; YG and PL wrote and edited the review; and HX critically edited the work.

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Guo, YJ., Xiong, H., Chen, K. et al. Brain regions susceptible to alpha-synuclein spreading. Mol Psychiatry 27, 758–770 (2022). https://doi.org/10.1038/s41380-021-01296-7

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