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Programmed Death-1 Deficiency Aggravates Motor Dysfunction in MPTP Model of Parkinson's Disease by Inducing Microglial Activation and Neuroinflammation in Mice

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Abstract

Abundant reactive gliosis and neuroinflammation are typical pathogenetic hallmarks of brains in Parkinson’s disease (PD) patients, but regulation mechanisms are poorly understood. We are interested in role of programmed death-1 (PD-1) in glial reaction, neuroinflammation and neuronal injury in PD pathogenesis. Using PD mouse model and PD-1 knockout (KO) mice, we designed wild-type-control (WT-CON), WT-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (WT-MPTP), PD-1-KO-control (KO-CON) and PD-1-KO-MPTP (KO-MPTP), and observed motor dysfunction of animal, morphological distribution of PD-1-positive cells, dopaminergic neuronal injury, glial activation and generation of inflammatory cytokines in midbrains by motor behavior detection, immunohistochemistry and western blot. WT-MPTP mouse model exhibited decrease of PD-1/Iba1-positive microglial cells in the substantia nigra compared with WT-CON mice. By comparison of four groups, PD-1 deficiency showed exacerbation in motor dysfunction of animals, decreased expression of TH protein and TH-positive neuronal protrusions. PD-1 deficiency enhanced microglial activation, production of proinflammatory cytokines like inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β and interleukin-6, and expression and phosphorylation of AKT and ERK1/2 in the substantia nigra of MPTP model. We concluded that PD-1 deficiency could aggravate motor dysfunction of MPTP mouse model by inducing microglial activation and neuroinflammation in midbrains, suggesting that PD-1 signaling abnormality might be possibly involved in PD pathogenesis.

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Abbreviations

AD:

Alzheimer’s disease

ARG1:

Arginase 1

GFAP:

Glial fibrillary acidic protein

IFNγ:

Interferon-γ

IL-6:

Interleukin-6

IL-10:

Interleukin-10

iNOS:

Inducible nitric oxide synthase

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PD:

Parkinson’s disease

PD-1:

Programmed death receptor-1

PD-L1:

Programmed death ligand 1

TGF-β:

Transforming growth factor-beta

TNF-α:

Tumor necrosis factor-alpha

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31600830, 31371374 and 31760279).

Funding

This research was supported by grants from the National Natural Science Foundation of China (31600830, 31371374 and 31760279). The funding bodies had no role in the design of the study or in the collection, analysis and interpretation of the data in this manuscript. National Natural Science Foundation of China,31600830,Liang-Wei Chen, 31371374, Liang-Wei Chen

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Author notes

  1. Ying-Ying Cheng and Bei-Yu Chen authors have equal contributions

Authors and Affiliations

  1. Department of Anatomy, Histology and Embryology, The Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China

    Ying-Ying Cheng & Yin-Xiu Ding

  2. Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

    Ying-Ying Cheng & Bei-Yu Chen

  3. Department of Neurobiology, Institute of Neurosciences, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

    Ying-Ying Cheng & Liang-Wei Chen

  4. Department of Histology and Embryology, School of Medicine, Northwest University, Xi’an, 710069, People’s Republic of China

    Gan-Lan Bian & Liang-Wei Chen

  5. Institute of Medical Research, Northwest Polytechnical University, Xi’an,, 710072, People’s Republic of China

    Gan-Lan Bian

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  1. Ying-Ying Cheng
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Contributions

Ying-Ying Cheng and Bei-Yu Chen were involved in methodology, writing and preparing the original draft.

Gan-Lan Bian carried out formal analysis and validation.

Liang-Wei Chen and Yin-Xiu Ding contributed to conceptualization, and writing, reviewing and editing.

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Correspondence to Yin-Xiu Ding or Liang-Wei Chen.

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Animal experiments were conducted in accordance with the National Institute of Health guide for the care and use of Laboratory animals (NIH Publications, eighth edition revised in 2012) and under the approval of the Animal Experiment Administration Committee of the Fourth Military Medical University.

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Cheng, YY., Chen, BY., Bian, GL. et al. Programmed Death-1 Deficiency Aggravates Motor Dysfunction in MPTP Model of Parkinson's Disease by Inducing Microglial Activation and Neuroinflammation in Mice. Mol Neurobiol 59, 2642–2655 (2022). https://doi.org/10.1007/s12035-022-02758-x

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