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2017 ; 8
(6
): e2854
Nephropedia Template TP
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Cystatin C as a potential therapeutic mediator against Parkinson s disease via
VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units
#MMPMID28569795
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
Cell Death Dis
2017[Jun]; 8
(6
): e2854
PMID28569795
show ga
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 ?-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-?/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.