Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units.
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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胱抑素 C 通过 VEGF 诱导的血管生成和增强神经血管单元中的神经元自噬作为潜在的帕金森病治疗介质
DOI：
10.1038/cddis.2017.240
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发表时间：
2017-06-01
影响因子：
9
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
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
胱抑素C（Cystatin C，Cst 3）是一种内源性半胱氨酸蛋白酶抑制剂，在神经退行性疾病中起神经保护作用。我们的目的是探索CYS C与帕金森病（PD）模型的相关性，并研究其参与神经血管单位（NVU）在PD神经发病机制中的作用。我们使用A53 T α-synuclein（SNCA）转基因小鼠和6-羟基多巴胺损伤的DA能PC 12细胞作为实验性PD模型来研究这种关联背后的机制。将CYS C注射到A53 T SNCA转基因小鼠的右侧黑质（SN）以测量CYS C在转基因A53 T SNCA小鼠中的作用。采用鸡胚绒毛尿囊膜（CAM）法和试管形成（TF）法研究了体内、外血管生成的情况。我们发现CYSC在这种体内PD模型中具有神经保护作用。我们观察到在CYSC处理的A53 T SNCA转基因小鼠的不同脑区域中VEGF、CD 3R 1和自噬标记物LC 3B增加，SNCA和凋亡标记物切割的CASP 3减少。在体外，我们观察到CYSC诱导的VEGF（一种分泌蛋白）通过调节p-PKC-α/p-ERK 1/2-Nurr 1信号通路和诱导自噬来减轻6-OHDA损伤的DA能PC 1/2细胞变性。VEGF介导的血管生成显着增强6-OHDA损伤的PC 12细胞与CYS C-过表达的条件培养基，而CYS C-过表达的PC 12细胞中的自噬的阻断显着下调VEGF的表达和相关的血管生成。我们的数据表明，CYS C显示双重神经血管功能，通过调节NVU中分泌的VEGF水平促进PC 12细胞存活和血管生成。我们的研究提供了证据，可能有助于开发一种通过调节CYS C介导的神经血管通路治疗PD的替代方法。
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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影响因子：
3.7
作者：
Kurz A;Double KL;Lastres-Becker I;Tozzi A;Tantucci M;Bockhart V;Bonin M;García-Arencibia M;Nuber S;Schlaudraff F;Liss B;Fernández-Ruiz J;Gerlach M;Wüllner U;Lüddens H;Calabresi P;Auburger G;Gispert S
通讯作者：
Gispert S
影响因子：
9
作者：
Koch JC;Bitow F;Haack J;d'Hedouville Z;Zhang JN;Tönges L;Michel U;Oliveira LM;Jovin TM;Liman J;Tatenhorst L;Bähr M;Lingor P
通讯作者：
Lingor P
影响因子：
11
作者：
HUGHES, AJ;DANIEL, SE;LEES, AJ
通讯作者：
LEES, AJ
影响因子：
9
作者：
通讯作者：
--
影响因子：
3.7
作者：
Awuah PK;Rhieu BH;Singh S;Misse A;Monga SP
通讯作者：
Monga SP