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

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dc.creatorZou, Jing
dc.creatorChen, Zhaoyu
dc.creatorWei, Xiaobo
dc.creatorChen, Zhigang
dc.creatorFu, Yongmei
dc.creatorYang, Xiaoyan
dc.creatorChen, Dan
dc.creatorWang, Rui
dc.creatorJenner, Peter
dc.creatorLu, Jia-Hong
dc.creatorLi, Min
dc.creatorZhang, Zhuohua
dc.creatorTang, Beisha
dc.creatorJin, Kunlin
dc.creatorWang, Qing
dc.creator.orcid0000-0002-1336-348X (Jin, Kunlin)
dc.date.accessioned2022-09-09T14:08:40Z
dc.date.available2022-09-09T14:08:40Z
dc.date.issued2017-06-01
dc.description.abstractCystatin 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 alpha-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-alpha/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.
dc.description.sponsorshipThis work was supported by the National Natural Science Foundation of China (Grant No: 81271427, 81471291), 973 Project (2011CB510000), Natural Science Foundations of Guangdong of China (2014A020212068), Science and Technology Program of Guangdong of China (2016A050502019), Fundamental Research Funds for the Central Universities (Grant No.: 16ykjc22), and Scientific Research Foundation of Guangzhou (Grant No.: 2014J4100210) to QW. ZZ and BTwere supported by 973 Project (2011CB510000).
dc.identifier.citationZou, J., Chen, Z., Wei, X., Chen, Z., Fu, Y., Yang, X., Chen, D., Wang, R., Jenner, P., Lu, J. H., 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, 8(6), e2854. https://doi.org/10.1038/cddis.2017.240
dc.identifier.issn2041-4889 (Electronic)
dc.identifier.issue6
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31691
dc.identifier.volume8
dc.publisherSpringer Nature
dc.relation.urihttps://doi.org/10.1038/cddis.2017.240
dc.rights.holder© The Author(s) 2017.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceCell Death & Disease
dc.subject.meshAnimals
dc.subject.meshAutophagy / drug effects
dc.subject.meshCaspase 3 / genetics
dc.subject.meshCaspase 3 / metabolism
dc.subject.meshChick Embryo
dc.subject.meshChorioallantoic Membrane / blood supply
dc.subject.meshChorioallantoic Membrane / drug effects
dc.subject.meshChorioallantoic Membrane / metabolism
dc.subject.meshCystatin C / pharmacology
dc.subject.meshDisease Models, Animal
dc.subject.meshGene Expression Regulation
dc.subject.meshHumans
dc.subject.meshInjections, Intraventricular
dc.subject.meshMice
dc.subject.meshMice, Transgenic
dc.subject.meshMicrotubule-Associated Proteins / genetics
dc.subject.meshMicrotubule-Associated Proteins / metabolism
dc.subject.meshNeovascularization, Physiologic / drug effects
dc.subject.meshNeurons / drug effects
dc.subject.meshNeurons / metabolism
dc.subject.meshNeurons / pathology
dc.subject.meshNeuroprotective Agents / pharmacology
dc.subject.meshNuclear Receptor Subfamily 4, Group A, Member 2 / genetics
dc.subject.meshNuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
dc.subject.meshOxidopamine / antagonists & inhibitors
dc.subject.meshOxidopamine / pharmacology
dc.subject.meshPC12 Cells
dc.subject.meshParkinson Disease / genetics
dc.subject.meshParkinson Disease / metabolism
dc.subject.meshParkinson Disease / pathology
dc.subject.meshRats
dc.subject.meshSignal Transduction
dc.subject.meshSubstantia Nigra / drug effects
dc.subject.meshSubstantia Nigra / metabolism
dc.subject.meshSubstantia Nigra / pathology
dc.subject.meshVascular Endothelial Growth Factor A / genetics
dc.subject.meshVascular Endothelial Growth Factor A / metabolism
dc.subject.meshalpha-Synuclein / genetics
dc.subject.meshalpha-Synuclein / metabolism
dc.titleCystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units
dc.typeArticle
dc.type.materialtext

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