Neuron
Volume 103, Issue 4, 21 August 2019, Pages 627-641.e7
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Article
Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease

https://doi.org/10.1016/j.neuron.2019.05.035Get rights and content
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Highlights

  • Gut-to-brain propagation of pathologic α-synuclein via the vagus nerve causes PD

  • Dopamine neurons degenerate in the pathologic α-synuclein gut-to-brain model of PD

  • Gut injection of pathologic α-synuclein causes PD-like motor and non-motor symptoms

  • PD-like pathology and symptoms require endogenous α-synuclein

Summary

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).

Keywords

Parkinson’s disease
α-synuclein
Lewy body pathology
gut to brain transmission
vagus nerve
neurodegeneration
motor symptoms
non-motor symptoms
pre-formed fibrils
Braak hypothesis

Cited by (0)

9

Present address: Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA

10

Present address: Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China

11

These authors contributed equally

12

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