Abstract
The current study investigated the physiological mechanisms by which extracellular vesicle (EV)-encapsulated miR-181a–2–3p derived from mesenchymal stem cells (MSCs) might mediate oxidative stress (OS) in Parkinson’s disease (PD). First, 6-hydroxydopamine (6-OHDA)-induced PD cell and mouse models were established, after which miR-181a–2–3p, EGR1, and NOX4 expression patterns were determined in SH-SY5Y cells and substantia nigra (SN) of PD mice. Next, the binding affinity among miR-181a–2–3p, EGR1, and NOX4 was identified using multiple assays. Gain- or loss-of-function experiments were further adopted to detect SH-SY5Y cell proliferation and apoptosis and to measure the levels of SOD, MDA, and ROS. Finally, the effects of miR-181a–2–3p from MSC-derived EVs in PD mouse models were also explored. It was found that miR-181a–2–3p was poorly expressed in 6-OHDA-induced SH-SY5Y cells, whereas miR-181a–2–3p from MSCs could be transferred into SH-SY5Y cells via EVs. In addition, miR-181a–2–3p could target and inhibit EGR1, which promoted the expression of NOX4. The aforementioned miR-181a–2–3p shuttled by MSC-derived EVs facilitated SH-SY5Y proliferation and SOD levels, but suppressed apoptosis and MDA and ROS levels by regulating EGR1 via inhibition of NOX4/p38 MAPK, so as to repress OS of PD. Furthermore, in PD mice, miR-181a–2–3p was carried by EVs from MSCs to alleviate apoptosis of dopamine neurons and OS, accompanied by increased expressions of α-syn and decreased 4-HNE in SN tissues. Collectively, our findings revealed that MSC-derived EV-loaded miR-181a–2–3p downregulated EGR1 to inhibit OS via the NOX4/p38 MAPK axis in PD.
Highlights
Parkinson’s disease (PD), one of the leading chronic degenerative neurological forms of dyskinesia, poses a significant threat to the health of elderly populations [1]
The results of reverse-transcription quantitative polymerase-chain reaction (RT-qPCR) demonstrated that miR181a–2–3p expression levels were decreased in 6-OHDA-treated SH-SY5Y cells, while being increased in cells transduced with miR181a–2–3p mimic, verifying the successful transduction efficiency (Fig. 1G)
As illustrated by cell-counting kit (CCK)-8 and flow cytometry, cell viability was decreased and apoptosis was increased in 6-OHDA-treated SH-SY5Y cells, while the opposite trends were observed in cells transduced with miR-181a–2–3p mimic (Fig. 1H, I)
Summary
Parkinson’s disease (PD), one of the leading chronic degenerative neurological forms of dyskinesia, poses a significant threat to the health of elderly populations [1]. PD is characterized by a plethora of cellular abnormalities, including oxidative stress (OS), proteasome stress, and mitochondrial dysfunction [2]. OS is well-established to function as a key factor for cell dysfunction and death in PD [3], and further serves as the imbalance between reactive oxygen species and the ability of cells to produce an effective antioxidant response [4]. The last decade has witnessed the discovery of the therapeutic potential of mesenchymal stem cells (MSC) in neurodegenerative disorders, including PD [5]. MSCs possess the ability to transfer specific types of extracellular vesicles (EVs) to achieve therapeutic effects [6]. MSC–EVs have been previously highlighted as a potential target for treating PD [7], the specific mechanisms of MSC-derived EVs underlying in OS in PD remain to be further elucidated
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