Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units

Jing Zou, Zhaoyu Chen, Xiaobo Wei, Zhigang Chen, Yongmei Fu, Xiaoyan Yang, Dan Chen, Rui Wang, Peter Jenner, Jia Hong Lu, Min Li, Zhuohua Zhang, Beisha Tang, Kunlin Jin, Qing Wang

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Abstract

Cystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson's disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α-synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro, we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro, we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal-vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.

Original languageEnglish
Pages (from-to)e2854
JournalCell death & disease
Volume8
Issue number6
DOIs
StatePublished - 1 Jun 2017

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Cystatin C
PC12 Cells
Autophagy
Vascular Endothelial Growth Factor A
Parkinson Disease
Oxidopamine
Transgenic Mice
Blood Vessels
Synucleins
Cysteine Proteinase Inhibitors
Therapeutics
Chorioallantoic Membrane
Parkinsonian Disorders
Neuroprotective Agents
Substantia Nigra
Chick Embryo
Conditioned Culture Medium
Caspase 3
Neurodegenerative Diseases
Cell Survival

Cite this

Zou, Jing ; Chen, Zhaoyu ; Wei, Xiaobo ; Chen, Zhigang ; Fu, Yongmei ; Yang, Xiaoyan ; Chen, Dan ; Wang, Rui ; Jenner, Peter ; Lu, Jia Hong ; Li, Min ; Zhang, Zhuohua ; Tang, Beisha ; Jin, Kunlin ; Wang, Qing. / Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units. In: Cell death & disease. 2017 ; Vol. 8, No. 6. pp. e2854.
@article{4223411aeade47eca88e52cfe5cf34bd,
title = "Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units",
abstract = "Cystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson's disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α-synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro, we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro, we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal-vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.",
author = "Jing Zou and Zhaoyu Chen and Xiaobo Wei and Zhigang Chen and Yongmei Fu and Xiaoyan Yang and Dan Chen and Rui Wang and Peter Jenner and Lu, {Jia Hong} and Min Li and Zhuohua Zhang and Beisha Tang and Kunlin Jin and Qing Wang",
year = "2017",
month = "6",
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doi = "10.1038/cddis.2017.240",
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Zou, J, Chen, Z, Wei, X, Chen, Z, Fu, Y, Yang, X, Chen, D, Wang, R, Jenner, P, Lu, JH, Li, M, Zhang, Z, Tang, B, Jin, K & Wang, Q 2017, 'Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units', Cell death & disease, vol. 8, no. 6, pp. e2854. https://doi.org/10.1038/cddis.2017.240

Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units. / Zou, Jing; Chen, Zhaoyu; Wei, Xiaobo; Chen, Zhigang; Fu, Yongmei; Yang, Xiaoyan; Chen, Dan; Wang, Rui; Jenner, Peter; Lu, Jia Hong; Li, Min; Zhang, Zhuohua; Tang, Beisha; Jin, Kunlin; Wang, Qing.

In: Cell death & disease, Vol. 8, No. 6, 01.06.2017, p. e2854.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units

AU - Zou, Jing

AU - Chen, Zhaoyu

AU - Wei, Xiaobo

AU - Chen, Zhigang

AU - Fu, Yongmei

AU - Yang, Xiaoyan

AU - Chen, Dan

AU - Wang, Rui

AU - Jenner, Peter

AU - Lu, Jia Hong

AU - Li, Min

AU - Zhang, Zhuohua

AU - Tang, Beisha

AU - Jin, Kunlin

AU - Wang, Qing

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Cystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson's disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α-synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro, we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro, we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal-vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.

AB - Cystatin C (CYS C, Cst3) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson's disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α-synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro, we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro, we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal-vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.

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U2 - 10.1038/cddis.2017.240

DO - 10.1038/cddis.2017.240

M3 - Article

VL - 8

SP - e2854

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 6

ER -