Journal Article

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

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

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/1 / 13/109 / 13/2 / 13/44 / 13/95 / 14/19 / 14/28 / 6-Hydroxydopamine / 631/378/1689/1718 / 631/443/592/16 / 631/80/82/39 / 692/700/565 / 82/80 / 96 / alpha-Synuclein - genetics / alpha-Synuclein - metabolism / Angiogenesis / Animal models / Animals / Antibodies / Apoptosis / Autophagy / Autophagy - drug effects / Biochemistry / Biomedical and Life Sciences / Caspase 3 - genetics / Caspase 3 - metabolism / Cell Biology / Cell Culture / Cell survival / Chick Embryo / Chorioallantoic membrane / Chorioallantoic Membrane - blood supply / Chorioallantoic Membrane - drug effects / Chorioallantoic Membrane - metabolism / Cystatin C / Cystatin C - pharmacology / Cysteine / Cysteine proteinase / Disease Models, Animal / Gene Expression Regulation / Humans / Immunology / Injections, Intraventricular / Life Sciences / Mice / Mice, Transgenic / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - metabolism / Movement disorders / Neovascularization, Physiologic - drug effects / Neurodegeneration / Neurodegenerative diseases / Neuromodulation / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Neuroprotection / Neuroprotective Agents - pharmacology / Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics / Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism / Nuclear receptors / Nurr1 protein / Original / original-article / Oxidopamine - antagonists & inhibitors / Oxidopamine - pharmacology / Parkinson Disease - genetics / Parkinson Disease - metabolism / Parkinson Disease - pathology / Parkinson's disease / PC12 Cells / Phagocytosis / Proteinase / Rats / Signal Transduction / Substantia Nigra - drug effects / Substantia Nigra - metabolism / Substantia Nigra - pathology / Survival / Synuclein / Transgenic animals / Transgenic mice / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism