Brain endothelial p-glycoprotein level is reduced in parkinson’s disease via a vitamin d receptor-dependent pathway
- Authors
- Kim, H.; Shin, J.-Y.; Lee, Y.-S.; Yun, S.P.; Maeng, H.-J.; Lee, Y.
- Issue Date
- Nov-2020
- Publisher
- MDPI AG
- Keywords
- 6-hydroxydopamine; Brain endothelium; P-glycoprotein; Parkinson’s disease; Vitamin D receptor; α-synuclein aggregation
- Citation
- International Journal of Molecular Sciences, v.21, no.22, pp.1 - 15
- Journal Title
- International Journal of Molecular Sciences
- Volume
- 21
- Number
- 22
- Start Page
- 1
- End Page
- 15
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/79354
- DOI
- 10.3390/ijms21228538
- ISSN
- 1661-6596
- Abstract
- The progressive neurodegeneration in Parkinson’s disease (PD) is accompanied by neuroinflammation and endothelial vascular impairment. Although the vitamin D receptor (VDR) is expressed in both dopamine neurons and brain endothelial cells, its role in the regulation of endothelial biology has not been explored in the context of PD. In a 6-hydroxydopamine (6-OHDA)-induced PD mouse model, we observed reduced transcription of the VDR and its downstream target genes, CYP24 and MDR1a. The 6-OHDA-induced transcriptional repression of these genes were recovered after the VDR ligand—1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment. Similarly, reduced vascular protein expression of P-glycoprotein (P-gp), encoded by MDR1a, after 6-OHDA administration was reversed by 1,25(OH)2D3. Moreover, marked reduction of endothelial P-gp expression with concomitant α-synuclein aggregation was found in a combinatorial AAV-αSyn/αSyn preformed fibril (PFF) injection mouse model and postmortem PD brains. Supporting the direct effect of α-synuclein aggregation on endothelial biology, PFF treatment of human umbilical vein endothelial cells (HUVECs) was sufficient to induce α-synuclein aggregation and repress transcription of the VDR. PFF-induced P-gp downregulation and impaired functional activity in HUVECs completely recovered after 1,25(OH)2D3 treatment. Taken together, our results suggest that a dysfunctional VDR-P-gp pathway could be a potential target for the maintenance of vascular homeostasis in PD pathological conditions. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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