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Engrafted primary type-2 astrocytes improve the recovery of the nigrostriatal pathway in a rat model of Parkinson's disease

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Abstract

Parkinson’s disease (PD) is a disorder characterized by a progressive loss of the dopaminergic neurons in the substantia nigra and a depletion of the neurotransmitter dopamine in the striatum. Our published results indicate that fasciculation and elongation protein zeta-1 (FEZ1) plays a role in the astrocyte-mediated protection of dopamine neurons and regulation of the neuronal microenvironment during the progression of PD. In this study, we examined the effects of engrafted type-2 astrocytes (T2As) with high expression of FEZ1 on the improvement of the symptoms and functional reconstruction of PD rats. T2As were stereotactically transplanted into the striatum of rats with PD induced by 6-hydroxydopamine (6-OHDA). An examination of apomorphine (APO)-induced rotations was performed to evaluate dopamine neuron damage and motor functions. Remarkably, the grafted cells survived in the lesion environment for six weeks or longer after implantation. In addition, the transplantation of T2As decrease the average velocity and the duration time of the APO-induced rotations, and increase the actuation time, as measured in the rotation behavioural tests. In the substantia nigra, the transplantation of T2As reduced the PD-induced GFAP, TH and FEZ1 downregulation. The grafted cells exclusively migrated to other regions near the injection site in the striatum and differentiated into GFAP+ astrocytes or TH+ neurons. Furthermore, by detecting monoamine neurotransmitters through high-performance liquid chromatography, we found that the nigrostriatal pathway had been repaired to some extent. Taken together, these results suggest that engrafted T2As with high expression of FEZ1 improved the symptoms and functional reconstruction of PD rats, providing a theoretical basis for FEZ1 as a potential target and engraftment of T2As as a therapeutic strategy in the treatment of PD.

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Abbreviations

PD:

Parkinson’s disease

FEZ1:

Fasciculation and elongation protein zeta-1

T2As:

Type-2 astrocytes

6-OHDA:

6-Hydroxydopamine

APO:

Apomorphine

DA:

Dopamine

5-HT:

5-Hydroxytryptamine

DOPAC:

Dihydroxy-phenyl acetic acid

HVA:

Homovanillic acid

O-2A:

Oligodendrocyte-type-2 astrocyte progenitor

ACSF:

Artificial cerebrospinal fluid

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81701316), by the Jiangsu Province Health Research Project (No. YG201307), and by Suzhou Science and Technology Plan (sys2018025, SYS2019025).

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Author notes

  1. Yanyun Sun and Xiao-jun Lu have contributed equally to this work.

Authors and Affiliations

  1. Boxi Institute of Clinical Anatomy and Cytoneurobiology Unit, Medical College of Soochow University, Suzhou, 215123, China

    Yanyun Sun, Xinghui Fu, Ye Zhang, Yan Zhan, Jiabing Liu, Lingxia Zhao & Chun-lin Xia

  2. Department of Neurology, First Peoples Hospital of Taicang, Taicang, Suzhou, China

    Xiao-jun Lu

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  1. Yanyun Sun
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Contributions

The work was performed and accomplished by all authors. CX are the principal investigators for the project design, the interpretation of results. YS, XL, XF, YEZ, YAZ, JL and LZ performed experiments, analysed the data, made the figures and drafted the manuscript. YS, CX and XL wrote the manuscript.

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Correspondence to Chun-lin Xia.

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Sun, Y., Lu, Xj., Fu, X. et al. Engrafted primary type-2 astrocytes improve the recovery of the nigrostriatal pathway in a rat model of Parkinson's disease. Mol Cell Biochem 476, 619–631 (2021). https://doi.org/10.1007/s11010-020-03931-3

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