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.
Highlights
Parkinson’s disease (PD) is mainly characterized by the rather selective and progressive demise of nigral dopaminergic neurons, which leads to the cardinal motor impairment in patients [1,2]
Data are expressed as mean ± standard error of the mean (SEM). ** p < 0.01, and *** p < 0.001, analysis of variance (ANOVA) test, followed by Tukey’s post hoc analysis. This is the first study to report on the molecular mechanism by which PD-relevant oxidative stress and α-synuclein aggregation influences brain vascular biology. 6-OHDA or preformed fibril (PFF) led to transcriptional repression of the vitamin D receptor (VDR) and its target genes, especially P-gp in mouse brains and in human umbilical vein endothelial cells (HUVECs)
6-OHDA-induced oxidative stress is known to prompt α-synuclein aggregation [29]
Summary
Parkinson’s disease (PD) is mainly characterized by the rather selective and progressive demise of nigral dopaminergic neurons, which leads to the cardinal motor impairment in patients [1,2]. As the main component of Lewy bodies or Lewy neurites, which are the diagnostic hallmark of PD and related α-synucleinopathies, pathological α-synuclein aggregates can propagate into many brain regions and interact with diverse cell types [5,6,7]. In addition to its effect on neurons, α-synuclein aggregates bind to the Toll-like receptor (TLR) expressed on microglia [5]. Studies have found pathological alteration of endothelial cells lining the cerebral blood vessels in PD [9,10]. In a previous study, α-synuclein PFF treatment of cultured cerebral endothelial cells led to altered expression of tight junction proteins [11], suggesting a pathological role of α-synuclein pathology in endothelial function. P-gp downregulation and deficits have been reported in postmortem PD brain samples [14,15], its underlying mechanisms are largely unexplored
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