ArticleToxicological sciences : an official journal of the Society of Toxicology2015
α-Synuclein protects against manganese neurotoxic insult during the early stages of exposure in a dopaminergic cell model of Parkinson's disease.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
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67 citing papers in PubMed, 1 synthesis or guideline pooled it, 98 citations in OpenAlex.
- Hypoxia and Alpha-Synuclein: Inextricable Link Underlying the Pathologic Progression of Parkinson's Disease.Frontiers in aging neuroscience · 2022Pooled it
- Protein Kinase C-delta (PKCδ) in Neurodegeneration and Cerebral Ischemia: Molecular Mechanisms and Therapeutic Implications.Cell biochemistry and biophysics · 2026Review
- Revisiting cirrhosis-related parkinsonism: a comprehensive review.Metabolic brain disease · 2026Review
- Article
- An iPSC-derived neuronal model reveals manganese's role in neuronal endocytosis, calcium flux and mitochondrial bioenergetics.iScience · 2025Article
- In vivo and in silico models of Drosophila for Parkinson's disease.The FEBS journal · 2025Review
- Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders.Journal of xenobiotics · 2025Review
- Biotin mitigates the development of manganese-induced, Parkinson's disease-related neurotoxicity inScience signaling · 2025Article
- Gut to brain: essential micronutrient and trace element manganese transport, function and toxicity.Frontiers in physiology · 2025Review
- Alpha-synuclein expression in neurons modulates Japanese encephalitis virus infection.Journal of virology · 2024Article
- Neuroprotective effects of punicalagin and/or micronized zeolite clinoptilolite on manganese-induced Parkinson's disease in a rat model: Involvement of multiple pathways.CNS neuroscience & therapeutics · 2024Article
- Neuronal Vulnerability to Degeneration in Parkinson's Disease and Therapeutic Approaches.CNS & neurological disorders drug targets · 2024Review
- Consequences of Disturbing Manganese Homeostasis.International journal of molecular sciences · 2023Review
- Manganese-Induced Parkinsonism: Evidence from Epidemiological and Experimental Studies.Biomolecules · 2023Review
- Impact of Environmental Risk Factors on Mitochondrial Dysfunction, Neuroinflammation, Protein Misfolding, and Oxidative Stress in the Etiopathogenesis of Parkinson's Disease.International journal of molecular sciences · 2022Review
- Building a Network of Adverse Outcome Pathways (AOPs) Incorporating the Tau-Driven AOP Toward Memory Loss (AOP429).Journal of Alzheimer's disease reports · 2022Review
- Parkinson's Disease and the Metal-Microbiome-Gut-Brain Axis: A Systems Toxicology Approach.Antioxidants (Basel, Switzerland) · 2021Review
- Ca2+ administration prevents α-synuclein proteotoxicity by stimulating calcineurin-dependent lysosomal proteolysis.PLoS genetics · 2021Article
- Stable expression of the human dopamine transporter in N27 cells as an in vitro model for dopamine cell trafficking and metabolism.Toxicology in vitro : an international journal published in association with BIBRA · 2021Article
- Chronic Manganese Exposure and the Enteric Nervous System: AnEnvironmental health perspectives · 2021Article
7 more citing papers are in PubMed but not listed here.
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5 authors at 1 institution in 1 country.
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Abstract
The pathological role of α-synuclein (α-Syn) aggregation in neurodegeneration is well recognized, but the physiological function of normal α-Syn remains unknown. As α-Syn protein contains multiple divalent metal binding sites, herein we conducted a comprehensive characterization of the role of α-Syn in manganese-induced dopaminergic neurotoxicity. We established transgenic N27 dopaminergic neuronal cells by stably expressing human wild-type α-Syn at normal physiological levels. α-Syn-expressing dopaminergic cells significantly attenuated Mn-induced neurotoxicity for 24-h exposures relative to vector control cells. To further explore cellular mechanisms, we studied the mitochondria-dependent apoptotic pathway. Analysis of a key mitochondrial apoptotic initiator, cytochrome c, revealed that α-Syn significantly reduces the Mn-induced cytochrome c release into cytosol. The downstream caspase cascade, involving caspase-9 and caspase-3 activation, during Mn exposure was also largely attenuated in Mn-treated α-Syn cells in a time-dependent manner. α-Syn cells also showed a dramatic reduction in the Mn-induced proteolytic activation of the pro-apoptotic kinase PKCδ. The generation of Mn-induced reactive oxygen species (ROS) did not differ between α-Syn and vector control cells, indicating that α-Syn exerts its protective effect independent of altering ROS generation. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed no significant differences in intracellular Mn levels between treated vector and α-Syn cells. Notably, the expression of wild-type α-Syn in primary mesencephalic cells also rescued cells from Mn-induced neurotoxicity. However, prolonged exposure to Mn promoted protein aggregation in α-Syn-expressing cells. Collectively, these results demonstrate that wild-type α-Syn exhibits neuroprotective effects against Mn-induced neurotoxicity during the early stages of exposure in a dopaminergic neuronal model of PD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.