Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice
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In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.
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Rotenone administered intragastrically in mice (5 mg/kg, 5 days a week, up to 3 months) induced accumulation of α-synuclein in several structures of the nervous system along with inflammation and α-synuclein phosphorylation in the ENS and the dorsal motor nucleus of the vagus.
“Rotenone (a pesticide) administered intragastrically in mice (5 mg/kg, 5 days a week, up to 3 months) induced accumulation of α-synuclein in several structures of the nervous system (i.e., dorsal motor nucleus of the vagus, intermediolateral nucleus of the spinal cord, the substantia nigra) along with inflammation and α-synuclein phosphorylation in the ENS and the dorsal motor nucleus of the vagus”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [405]
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- Authors
- Pan-Montojo, F., Anichtchik, O., Dening, Y., Knels, L., Pursche, S., Jung, R., Jackson, S., Gille, G., Spillantini, M. G., Reichmann, H., & Funk, R. H. W.
- Affiliations
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- University of Cambridge (GB)
- Technische Universität Dresden (DE)
- Corresponding author
- Pan-Montojo, Francisco
- Funk, Richard H. W.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-01-19
- Volume
- 5
- Issue
- 1
- Pages
- e8762
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2808242
- OpenAlex
- W2293877091
- Cited by
- 524
- References
- 64
- Citations by year
- 2026: 12 · 2025: 23 · 2024: 18 · 2023: 28 · 2022: 40 · 2021: 43 · 2020: 41 · 2019: 46 · 2018: 31 · 2017: 44 · 2016: 35 · 2015: 32 · 2014: 33 · 2013: 29 · 2012: 37
- FWCI
- 18.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Parkinson's UK (G-0701)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Parkinson's disease, rotenone, intragastric administration, alpha-synuclein accumulation, enteric nervous system, dorsal motor nucleus of the vagus, intermediolateral nucleus, substantia nigra, mitochondrial complex I inhibition, neuroinflammation, alpha-synuclein phosphorylation, pesticide exposure, disease staging, motor impairment, mouse model
- MeSH terms
- Animals, Chromatography, High Pressure Liquid, Disease Models, Animal, Mice, Inbred BALB C, Parkinson Disease, Rotenone, Stomach, Enteric Nervous System, Mice
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