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MPTP/MPP+ suppresses activation of protein C in Parkinson's disease

MPTP/MPP+ suppresses activation of protein C in Parkinson's disease
MPTP/MPP+ suppresses activation of protein C in Parkinson's disease
Endothelial dysfunction and disruption of the blood-brain barrier have been found to be associated with Parkinson's disease (PD). However, the mechanisms underlying these effects have yet to be elucidated. It has also been found that activated protein C (APC) displays neuroprotective properties. Presently, the effects of APC on PD remain unknown. Using a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxin rodent model of PD, we found that administration of MPTP can reduce expression of endothelial protein C receptor (EPCR), an N-glycosylated type I membrane protein that has the ability to enhance protein C activation. However, the use of MPTP does not alter levels of thrombomodulin. These findings were verified in an in vitro study showing that 1-methyl-4-phenylpyridinium (MPP+) treatment leads to suppression of EPCR along with reduction of protein C activation in human primary endothelial cells. Importantly, our results display that activation of the transcriptional factor SP1 is involved in the inhibitory effects of MPTP/MPP+ on EPCR expression. We found that using 300 nM of the SP1 inhibitor MIT can abolish the effects of MPP+ on EPCR expression. Consistently, SP1 silencing using small RNA interference was able to prevent the inhibitory effects of MPTP/MPP+ on the reduction of EPCR expression and impairment of protein C activation. Importantly, our results indicate that overexpression of SP1 inhibits EPCR promoter activity. Our study suggests that EPCR-APC may be a potential therapeutic target for endothelial dysfunction in PD
1387-2877
133-142
Chen, T.
24efad5a-bbfc-4f7f-ac60-344616765fe5
Hou, R.
470bdcbc-93a9-4dad-aac5-26d455c34376
Li, C.
1ee7b95a-ca14-41be-92fb-0d7a56252361
Wu, C.
3b3efc80-d865-49c5-80e8-6c6e687e6a78
Xu, S.
cc1b53e4-d014-4d72-9af3-073ea273e88f
Chen, T.
24efad5a-bbfc-4f7f-ac60-344616765fe5
Hou, R.
470bdcbc-93a9-4dad-aac5-26d455c34376
Li, C.
1ee7b95a-ca14-41be-92fb-0d7a56252361
Wu, C.
3b3efc80-d865-49c5-80e8-6c6e687e6a78
Xu, S.
cc1b53e4-d014-4d72-9af3-073ea273e88f

Chen, T., Hou, R., Li, C., Wu, C. and Xu, S. (2015) MPTP/MPP+ suppresses activation of protein C in Parkinson's disease. Journal of Alzheimer's Disease, 43 (1), 133-142. (doi:10.3233/JAD-140126). (PMID:25061051)

Record type: Article

Abstract

Endothelial dysfunction and disruption of the blood-brain barrier have been found to be associated with Parkinson's disease (PD). However, the mechanisms underlying these effects have yet to be elucidated. It has also been found that activated protein C (APC) displays neuroprotective properties. Presently, the effects of APC on PD remain unknown. Using a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxin rodent model of PD, we found that administration of MPTP can reduce expression of endothelial protein C receptor (EPCR), an N-glycosylated type I membrane protein that has the ability to enhance protein C activation. However, the use of MPTP does not alter levels of thrombomodulin. These findings were verified in an in vitro study showing that 1-methyl-4-phenylpyridinium (MPP+) treatment leads to suppression of EPCR along with reduction of protein C activation in human primary endothelial cells. Importantly, our results display that activation of the transcriptional factor SP1 is involved in the inhibitory effects of MPTP/MPP+ on EPCR expression. We found that using 300 nM of the SP1 inhibitor MIT can abolish the effects of MPP+ on EPCR expression. Consistently, SP1 silencing using small RNA interference was able to prevent the inhibitory effects of MPTP/MPP+ on the reduction of EPCR expression and impairment of protein C activation. Importantly, our results indicate that overexpression of SP1 inhibits EPCR promoter activity. Our study suggests that EPCR-APC may be a potential therapeutic target for endothelial dysfunction in PD

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More information

Accepted/In Press date: 26 May 2014
e-pub ahead of print date: 30 October 2014
Published date: 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 402717
URI: https://eprints.soton.ac.uk/id/eprint/402717
ISSN: 1387-2877
PURE UUID: 6226b2d1-b59a-4b1b-aab0-e1128dd2186d

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Date deposited: 14 Nov 2016 13:33
Last modified: 03 Aug 2018 16:33

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