Astragalus polysaccharide protects against neuron degeneration and mitochondrial dysfunction in Parkinson's disease by upregulating CEND1.
Astragalus polysaccharide protects against neuron degeneration and mitochondrial dysfunction in Parkinson's disease by upregulating CEND1.
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Original abstract
BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder featuring dopaminergic neuron loss, which is associated with mitochondrial dysfunction. Astragalus polysaccharide (APS) extracted from Astragalus membranaceus possesses antioxidant, anti-inflammatory, and neuroprotective properties. APS was previously revealed to exert neuroprotective effects in experimental PD models. However, the underlying mechanism remains poorly understood. Therefore, our study was designed to reveal the molecular mechanism through which APS exerts neuroprotective effects in PD. METHODS: SH-SY5Y cells were treated with 6-hydroxydopamine (6-OHDA) to induce the in vitro model of PD. 6-OHDA-treated SH-SY5Y cells were further transfected with sh-CEND1 and treated with APS to assess whether APS alleviates 6-OHDA-induced neurotoxicity through regulating CEND1. Cell viability, apoptosis, intracellular ROS levels, mitochondrial membrane potential (MMP), and the levels of dopaminergic neuronal markers and mitochondrial biogenesis-related proteins in SH-SY5Y cells were evaluated through a CCK-8 assay, flow cytometry, DCFH-DA staining, JC-1 staining, and western blotting. Finally, CEND1-knockout (CEND1-KO) mice were used to confirm whether APS exhibits the neuroprotective effects via a CEND1-dependent mechanism. Behavior tests, immunohistochemical staining, and western blotting were performed to examine mouse motor dysfunction, neuronal injury, and mitochondrial dysfunction. RESULTS: 6-OHDA downregulated CEND1 expression in SH-SY5Y cells and PD mice, which, however, was reversed after APS treatment. CEND1 knockdown aggravated while CEND1 overexpression ameliorated 6-OHDA-induced SH-SY5Y cell injury, apoptosis, ROS production, and mitochondrial dysfunction. The preventive effects of CEND1 upregulation against 6-OHDA-induced neuron degeneration and mitochondrial dysfunction were attributed to the activation of the PI3K/AKT and AMPK/SIRT1/PGC-1α signaling pathways. Besides, APS alleviated 6-OHDA-induced SH-SY5Y cell injury and mitochondrial dysfunction, while silencing of CEND1 abrogated the neuroprotective effects of APS in vitro. APS administration successfully improved motor deficits, neuronal injury, and mitochondrial impairments in WT (wild-type) mice, but failed to protect against PD in CEND1-KO mice. CONCLUSION: APS exerts its neuroprotective effects in PD by preventing mitochondrial dysfunction through increasing CEND1 expression.