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

Sangjune Kim; Seung-Hwan Kwon; Tae-In Kam; Nikhil Panicker; Senthilkumar S Karuppagounder; Saebom Lee; Jun Hee Lee; Wonjoong Richard Kim; Minjee Kook; Catherine A Foss; Chentian Shen; Hojae Lee; Subhash Kulkarni; Pankaj J Pasricha; Gabsang Lee; Martin G Pomper; Valina L Dawson; Ted M Dawson; Han Seok Ko

doi:10.1016/j.neuron.2019.05.035

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

Neuron. 2019 Aug 21;103(4):627-641.e7. doi: 10.1016/j.neuron.2019.05.035. Epub 2019 Jun 26.

Authors

Sangjune Kim¹, Seung-Hwan Kwon¹, Tae-In Kam¹, Nikhil Panicker¹, Senthilkumar S Karuppagounder¹, Saebom Lee¹, Jun Hee Lee¹, Wonjoong Richard Kim¹, Minjee Kook¹, Catherine A Foss², Chentian Shen², Hojae Lee¹, Subhash Kulkarni³, Pankaj J Pasricha³, Gabsang Lee⁴, Martin G Pomper², Valina L Dawson⁵, Ted M Dawson⁶, Han Seok Ko⁷

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Center for Neurogastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: tdawson@jhmi.edu.
⁷ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: hko3@jhmi.edu.

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).

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

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*
alpha-Synuclein / administration & dosage
alpha-Synuclein / deficiency
alpha-Synuclein / pharmacokinetics*
alpha-Synuclein / toxicity

Substances

Protein Aggregates
Snca protein, mouse
alpha-Synuclein

Abstract

Publication types

MeSH terms

Substances

Grants and funding