ArticleInternational journal of molecular sciences2024
Manganese Exposure Enhances the Release of Misfolded α-Synuclein via Exosomes by Impairing Endosomal Trafficking and Protein Degradation Mechanisms.
Article in International journal of molecular sciences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 1 of them a synthesis that pooled it.
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Who cites it
6 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Actual Data on Essential Trace Elements in Parkinson's Disease.Nutrients · 2025Pooled it
- Development of a Novel Extracellular Vesicle-Based Biomarker Approach for Pediatric High-Grade Glioma.Journal of extracellular biology · 2026Article
- Molecular mechanisms of SLC30A10-mediated manganese transport.Nature communications · 2025Article
- Manganese exposure: a study on apoptosis and Ferroptosis in mouse Leydig and Sertoli cells.Toxicology research · 2025Article
- Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases.Frontiers in cellular neuroscience · 2025Article
- Gut to brain: essential micronutrient and trace element manganese transport, function and toxicity.Frontiers in physiology · 2025Review
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Authors and funding
16 authors.
Funding
Abstract
Excessive exposure to manganese (Mn) increases the risk of chronic neurological diseases, including Parkinson's disease (PD) and other related Parkinsonisms. Aggregated α-synuclein (αSyn), a hallmark of PD, can spread to neighboring cells by exosomal release from neurons. We previously discovered that Mn enhances its spread, triggering neuroinflammatory and neurodegenerative processes. To better understand the Mn-induced release of exosomal αSyn, we examined the effect of Mn on endosomal trafficking and misfolded protein degradation. Exposing MN9D dopaminergic neuronal cells stably expressing human wild-type (WT) αSyn to 300 μM Mn for 24 h significantly suppressed protein and mRNA expression of Rab11a, thereby downregulating endosomal recycling, forcing late endosomes to mature into multivesicular bodies (MVBs). Ectopic expression of WT Rab11a significantly mitigated exosome release, whereas ectopic mutant Rab11a (S25N) increased it. Our in vitro and in vivo studies reveal that Mn exposure upregulated (1) mRNA and protein levels of endosomal Rab27a, which mediates the fusion of MVBs with the plasma membrane; and (2) expression of the autophagosomal markers Beclin-1 and p62, but downregulated the lysosomal marker LAMP2, thereby impairing autophagolysosome formation as confirmed by LysoTracker, cathepsin, and acridine orange assays. Our novel findings demonstrate that Mn promotes the exosomal release of misfolded αSyn by impairing endosomal trafficking and protein degradation.
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Registered trials
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