期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 22, 页码 -出版社
MDPI
DOI: 10.3390/ijms21228538
关键词
vitamin D receptor; Parkinson’ s disease; P-glycoprotein; 6-hydroxydopamine; brain endothelium; α -synuclein aggregation
资金
- National Research Foundation (NRF) by the Ministry of Science, ICT, & Future Planning [2017M3C7A1043848, NRF-2019R1F1A1058103]
- National Institute of Neurological Disorders and Stroke [U24 NS072026]
- National Institute of Aging [P30 AG19610]
- Arizona Department of Health Services [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research
- National Research Foundation of Korea [2017M3C7A1043848] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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-1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) treatment. Similarly, reduced vascular protein expression of P-glycoprotein (P-gp), encoded by MDR1a, after 6-OHDA administration was reversed by 1,25(OH)(2)D-3. Moreover, marked reduction of endothelial P-gp expression with concomitant alpha-synuclein aggregation was found in a combinatorial AAV-alpha Syn/alpha Syn preformed fibril (PFF) injection mouse model and postmortem PD brains. Supporting the direct effect of alpha-synuclein aggregation on endothelial biology, PFF treatment of human umbilical vein endothelial cells (HUVECs) was sufficient to induce alpha-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)(2)D-3 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.
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