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Exogenous Tetranectin Alleviates Pre-formed-fibrils-induced Synucleinopathies in SH-SY5Y Cells by Activating the Plasminogen Activation System

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Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease. Previously we identified tetranectin (TN) as a differentially expressed protein in the cerebrospinal fluid of PD patients, and we were surprised to find that TN knockout mice developed PD features. However, the specific role of TN in PD has not been clarified. In this study, we aimed to determine the effect of exogenous TN on cellular PD models and elucidate the underlying mechanisms. We found that exogenous TN could alleviate pre-formed-fibrils (PFFs)-induced synucleinopathies in SH-SY5Y cells and reduce the cell-to-cell transmission of α-synuclein (SYN). We also found that TN can promote the degradation of SYN by plasmin, which may account for its effect on cellular PD models. Moreover, administration of SYN/PFFs decreased the expression of TN and increased the expression of plasminogen activator inhibitor-1 (PAI-1) in SH-SY5Y cells, thereby reducing plasmin activity. Our findings depict a possible SYN-TN-plasmin interaction in which elevated levels of extracellular SYN monomers and aggregates in PD diminish the production of TN and PAI-1. Such changes lead to a reduced plasmin activity, which in turn reduces the degradation of extracellular SYN, thus forming a vicious cycle.

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Data Availability

Relevant data and materials in the current study are available from the corresponding author on reasonable request.

Abbreviations

PD:

Parkinson’s disease

PFF(s):

Pre-formed Fibrils

TN:

Tetranectin

eTN:

Exogenous tetranectin

SYN:

α-Synuclein

SNc:

Substantia Nigra Pars Compacta

LBs:

Lewy Bodies

CSF:

Cerebrospinal fluid

PAI-1:

Plasminogen activator inhibitor-1

PLN:

Plasmin

PLG:

Plasminogen

PAS:

Plasminogen activation system

t-PA:

Tissue-type plasminogen activator

u-PA:

Urine plasminogen activator

CNS:

Central nervous system

WT:

Wild type

pS129:

α-Synuclein phosphorylated at serine 129

MMP-3:

Matrix metalloproteinases-3

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Funding

This work was supported by grants from the Health Commission of Jinshan District (Grant No. JSZK2019H02) to Ersong Wang, and the Science and Technology Commission of Jinshan District (Grant No. 2018-3-7) to Ri Tang.

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Author notes

  1. Heng Lin and Ri Tang have contributed to this work equally as co-first authors.

Authors and Affiliations

  1. Department of Neurosurgery, Jinshan Hospital, Fudan University, Shanghai, 201508, China

    Heng Lin, Ri Tang, Lijun Fan & Ersong Wang

  2. Department of Critical Care Medicine, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, 200127, China

    Ri Tang

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  1. Heng Lin
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  2. Ri Tang
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  3. Lijun Fan
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  4. Ersong Wang
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Contributions

All the authors contributed to the conception and design. HL: Performed the experiments and data analysis. EW and RT: Acquired the funding. HL: Wrote the first draft of the manuscript, and all authors commented on the previous version of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ersong Wang.

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Lin, H., Tang, R., Fan, L. et al. Exogenous Tetranectin Alleviates Pre-formed-fibrils-induced Synucleinopathies in SH-SY5Y Cells by Activating the Plasminogen Activation System. Neurochem Res 47, 3192–3201 (2022). https://doi.org/10.1007/s11064-022-03673-2

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  • DOI: https://doi.org/10.1007/s11064-022-03673-2

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