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Angiotensin-(1-7) relieves behavioral defects and α-synuclein expression through NEAT1/miR-153-3p axis in Parkinson’s disease

ABSTRACT: Parkinson's disease is the second most common neurodegenerative disorder, whose characteristic pathology involves progressive loss of dopaminergic neurons and formation of Lewy bodies(LBs) in the substantia nigra(SN). Aggregated and misfolded α-synuclein(α-syn) is the major constituent of LBs. As the newly discovered pathway of renin-angiotensin system (RAS), Angiotensin-(1-7)(Ang-(1-7)) and its receptor Mas have attracted increasing attentions for their correlation with PD progression, but underlying mechanisms remain not very clear. Based on the above, this study established PD models of mice and primary dopaminergic neurons with overexpression of α-syn, then discussed the effect of Ang-(1-7)/Mas on these models combined with downstream lncRNA and miRNA. The findings show that Ang-(1-7) alleviates behavioral disorders, rescues dopaminergic neurons loss and lowers α-syn expression in the SN of hα-syn(A53T) overexpressed PD mice. We also discover that Ang-(1-7) decreases the level of α-syn and apoptosis in the hα-syn(A53T) overexpressed dopaminergic neurons through NEAT1/miR-153-3p axis. Moreover, miR-153-3p expression in peripheral blood is found negatively correlated with that of α-syn. These results not only uncovered the significance and related mechanisms of Ang-(1-7)/Mas on α-syn pathology, but also throwed a new light upon miR-153-3p and NEAT1 as biomarkers and therapeutic targets in PD.

ORGANISM(S): Mus musculus

PROVIDER: GSE248268 | GEO | 2025/01/15

REPOSITORIES: GEO

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Project description:Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.

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Angiotensin-(1-7) relieves behavioral defects and α-synuclein expression through NEAT1/miR-153-3p axis in Parkinson’s disease

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