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Interaction Between the Glymphatic System and α-Synuclein in Parkinson’s Disease

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Abstract

The glymphatic system contributes to the clearance of amyloid-β from the brain and is disrupted in Alzheimer’s disease. However, whether the system is involved in the removal of α-synuclein (α-syn) and whether it is suppressed in Parkinson’s disease (PD) remain largely unknown. In mice receiving the intranigral injection of recombinant human α-syn, we found that the glymphatic suppression via aquaporin-4 (AQP4) gene deletion or acetazolamide treatment reduced the clearance of injected α-syn from the brain. In mice overexpressing the human A53T-α-syn, we revealed that AQP4 deficiency accelerated the accumulation of α-syn, facilitated the loss of dopaminergic neurons, and accelerated PD-like symptoms. We also found that the overexpression of A53T-α-syn reduced the expression/polarization of AQP4 and suppressed the glymphatic activity of mice. The study demonstrates a close interaction between the AQP4-mediated glymphatic system and parenchymal α-syn, indicating that restoring the glymphatic activity is a potential therapeutic target to delay PD progression.

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Data Availability

All data generated or analyzed during the current study are included in this article.

Abbreviations

AQP4:

Aquaporin-4

α-syn:

α-Synuclein

PD:

Parkinson’s disease

AD:

Alzheimer’s disease

SN:

Substantia Nigra

LB:

Lewy body

LN:

Lewy neurite

CSF:

Cerebrospinal fluid

ISF:

Interstitial fluid

Aβ:

Amyloid-β

AAV:

Adeno-associated virus

AZA:

Acetazolamide

CM:

Cistern magna

OA-45:

Alexa 555-conjugated ovalbumin

PBS:

Phosphate-buffered saline

PFA:

Paraformaldehyde

DAPI:

DNase I and 4′,6-diamidine-2′-phenylindole dihydrochloride

NeuN:

Neuronal nuclei

GFAP:

Glial fibrillary acidic protein

Iba1:

Ionized calcium-binding adapter molecule 1

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor-α

IL-6:

Interleukin-6

NC:

Un-injected control

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Acknowledgements

We are grateful to Prof. Guang-Yin Xu for helpful discussion and technical support.

Funding

This work was supported by the National Natural Science Foundation of China (31871167), Shanghai Key Laboratory of Psychotic Disorders Open Grant (13dz2260500), Suzhou Science and Technology Research Project (SKJY2021121), and Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Author notes

  1. Yu Zhang and Cui Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Neurobiology, Suzhou Medical College of Soochow University, 199 Ren-Ai Road, Suzhou, 215123, People’s Republic of China

    Yu Zhang, Cui Zhang, Xu-Zhong He, Zhen-Hua Li, Jing-Cai Meng, Rui-Ting Mao, Xin Li, Rong Xue, Guo-Xing Zhang & Lin-Hui Wang

  2. Department of Neurology, Suzhou Municipal Hospital, 26 Dao-Qian Street, Suzhou, 215002, People’s Republic of China

    Qian Gui

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Contributions

YZ, CZ, XZH, ZHL, JCM, RTM, and RX performed experiments, YZ and CZ analyzed data and made figures, XL drew the schematic diagrams, QG and GXZ edited the paper, and LHW designed research and wrote the paper. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Lin-Hui Wang.

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All procedures were approved by the Committee on Animal Resources of Soochow University. All efforts were made to reduce the number and suffering of animals to a minimum.

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Zhang, Y., Zhang, C., He, XZ. et al. Interaction Between the Glymphatic System and α-Synuclein in Parkinson’s Disease. Mol Neurobiol 60, 2209–2222 (2023). https://doi.org/10.1007/s12035-023-03212-2

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