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

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 pref...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Vol. 103; no. 4; p. 627
Main Authors: Kim, Sangjune, Kwon, Seung-Hwan, Kam, Tae-In, Panicker, Nikhil, Karuppagounder, Senthilkumar S, Lee, Saebom, Lee, Jun Hee, Kim, Wonjoong Richard, Kook, Minjee, Foss, Catherine A, Shen, Chentian, Lee, Hojae, Kulkarni, Subhash, Pasricha, Pankaj J, Lee, Gabsang, Pomper, Martin G, Dawson, Valina L, Dawson, Ted M, Ko, Han Seok
Format: Journal Article
Language:English
Published: United States 21.08.2019
Subjects:
alpha-Synuclein - administration & dosage
alpha-Synuclein - deficiency
alpha-Synuclein - pharmacokinetics
alpha-Synuclein - toxicity
Animals
Axonal Transport
Brain Chemistry
Dopaminergic Neurons - metabolism
Dopaminergic Neurons - pathology
Duodenum - innervation
Duodenum - metabolism
Humans
Injections, Intramuscular
Lewy Bodies - metabolism
Maze Learning
Memory Disorders - etiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Neurological
Muscle, Smooth - innervation
Muscle, Smooth - metabolism
Nesting Behavior - physiology
Parkinsonian Disorders - etiology
Parkinsonian Disorders - metabolism
Parkinsonian Disorders - prevention & control
Parkinsonian Disorders - psychology
Phosphorylation
Protein Aggregates
Protein Processing, Post-Translational
Pylorus - innervation
Pylorus - metabolism
Rotarod Performance Test
Vagotomy
Vagus Nerve - metabolism
Lewy body pathology
vagus nerve
motor symptoms
Braak hypothesis
pre-formed fibrils
neurodegeneration
gut to brain transmission
non-motor symptoms
Parkinson’s disease
α-synuclein
ISSN:1097-4199, 1097-4199
Online Access:Get more information
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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).
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ISSN:1097-4199
1097-4199
DOI:10.1016/j.neuron.2019.05.035