ArticleActa neuropathologica2014
Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD.
Article in Acta neuropathologica, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- Parkinson disease-associated toxic exposures selectively up-regulate vesicular glutamate transporter vGlut2 in a model of human cortical neurons.Molecular biology of the cell · 2025Article
- Enhancements in Parkinson's Disease Management: Leveraging Levodopa Optimization and Surgical Breakthroughs.Current drug targets · 2025Review
- The Parkinson-Associated Toxin Paraquat Shifts Physiological α-Synuclein Tetramers toward Monomers That Can Be Calpain-Truncated and Form Oligomers.The American journal of pathology · 2023Article
- The Positive Role and Mechanism of Herbal Medicine in Parkinson's Disease.Oxidative medicine and cellular longevity · 2021Review
- Autophagy Stimulation Decreases Dopaminergic Neuronal Death Mediated by Oxidative Stress.Molecular neurobiology · 2019Article
- High Pesticide Exposure Events and Olfactory Impairment among U.S. Farmers.Environmental health perspectives · 2019Article
- Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond.BioMed research international · 2019Review
- Article
- MicroRNA-30e regulates neuroinflammation in MPTP model of Parkinson's disease by targeting Nlrp3.Human cell · 2018Article
- Clathrin-Dependent Uptake of Paraquat into SH-SY5Y Cells and Its Internalization into Different Subcellular Compartments.Neurotoxicity research · 2017Article
- Non-motor features of Parkinson disease.Nature reviews. Neuroscience · 2017Review
- Mechanisms of Gene-Environment Interactions in Parkinson's Disease.Current environmental health reports · 2017Review
- Therapeutic approaches in Parkinson's disease and related disorders.Journal of neurochemistry · 2016Review
- Caspase-1 clipping causes complications for α-synuclein.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- The Cytomegalovirus protein pUL37×1 targets mitochondria to mediate neuroprotection.Scientific reports · 2016Article
- Reducing Endogenous α-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
- MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease.Molecular neurodegeneration · 2016Article
- Accumulation of α-synuclein in dementia with Lewy bodies is associated with decline in the α-synuclein-degrading enzymes kallikrein-6 and calpain-1.Acta neuropathologica communications · 2014Article
- Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells.Molecular and cellular neurosciences · 2014Article
- Overexpression of the calpain-specific inhibitor calpastatin reduces human alpha-Synuclein processing, aggregation and synaptic impairment in [A30P]αSyn transgenic mice.Human molecular genetics · 2014Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
The olfactory bulb (OB) is one of the first brain regions in Parkinson's disease (PD) to contain alpha-synuclein (α-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for α-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory α-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant α-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory α-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread α-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of α-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed α-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble α-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human α-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD.
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