Cited by 1,397Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAlzheimer's disease research and treatments

Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease

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Kim, Sangjune, Kwon, Seung-Hwan, Kam, Tae-In, Panicker, Nikhil, Karuppagounder, Senthilkumar S., Lee, Saebom, Lee, Jun Hee, Kim, Wonjoong Richard +11 more·2019·Neuron

Abstract

Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).

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Crossref · 10.1016/j.neuron.2019.05.035

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  • Cellular and animal studies have provided a model for prion-like spread of α-synuclein from the gut to the brain via the enteric nervous system, chiefly through the vagus nerve.

    “Third, cellular and animal studies have provided a model for prion-like spread of α-synuclein from the gut to the brain via the enteric nervous system, chiefly through the vagus nerve [15–17].”
  • Vagotomy can prevent the transmission of pathological a-synuclein to the CNS in animal models.

    “Vagotomy can prevent the transmission of pathological a-synuclein to the CNS in animal models.137,138”
  • Truncal vagotomy prevents the spread of α-syn from the gut to the brain, which is associated with neurodegeneration and behavioural deficits.

    “Correspondingly, truncal vagotomy prevents the spread of α-syn from the gut to the brain, which is associated with neurodegeneration and behavioural deficits.241,242”
  • The pathology of PD might begin in the gut and gradually progress to the brain.

    “Braak et al. theorized that the pathology of PD might begin in the gut and gradually progress to the brain [14], which was partially supported by subsequent research [15]”
  • Gut injection with α-synuclein fibrils (12.5 μg) in mice systematically spread pathology upwards to the dorsal motor nucleus of the vagus, locus coeruleus, amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta, and induced motor and non-motor symptoms resembling Parkinson's disease.

    “Gut injection with α-synuclein fibrils (12.5 μg) in mice also systematically spread pathology “upwards”, i.e., to the dorsal motor nucleus of the vagus, locus coeruleus, amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta, and it induced motor and non-motor symptoms resembling Parkinson's disease [401].”

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Authors
Kim, S., Kwon, S.-H., Kam, T.-I., Panicker, N., Karuppagounder, S. S., Lee, S., Lee, J. H., Kim, W. R., Kook, M., Foss, C. A., Shen, C., Lee, H., Kulkarni, S., Pasricha, P. J., Lee, G., Pomper, M. G., Dawson, V. L., Dawson, T. M., & Ko, H. S.
Affiliations
Johns Hopkins University (US)
Corresponding author
  • Dawson, Ted M.
  • Ko, Han Seok
Venue
Neuron
Publisher
Elsevier BV
Published
2019-08
Volume
103
Issue
4
Pages
627-641.e7
ISSN
0896-6273 (ISSN-L)
OpenAlex
W2953534538
Cited by
1,397
References
83
Citations by year
2026: 175 · 2025: 205 · 2024: 198 · 2023: 167 · 2022: 224 · 2021: 210 · 2020: 171 · 2019: 47
FWCI
110.48
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • JPB Foundation
  • National Institutes of Health
  • Adrienne Helis Malvin Medical Research Foundation
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Parkinson's disease, alpha-synuclein, vagus nerve, Braak hypothesis, preformed fibrils, serine 129 phosphorylation, dorsal motor nucleus of the vagus, locus coeruleus, substantia nigra pars compacta, dopaminergic neuron loss, vagotomy, mouse model, neurodegeneration, motor and non-motor symptoms
MeSH terms
Animals, Axonal Transport, Brain Chemistry, Duodenum, Humans, Injections, Intramuscular, Memory Disorders, Mice, Inbred C57BL, Models, Neurological, Muscle, Smooth, Nesting Behavior, Phosphorylation, Protein Processing, Post-Translational, Pylorus, Vagotomy, Vagus Nerve, Lewy Bodies, Mice, Knockout, Maze Learning, Parkinsonian Disorders, Rotarod Performance Test, Mice, alpha-Synuclein, Dopaminergic Neurons, Protein Aggregates

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