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

• Published in: Neuron (Cambridge, Mass.) Vol. 103; no. 4; pp. 627 - 641.e7
• 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 Elsevier Inc 21.08.2019; Elsevier Limited
• Subjects: alpha-Synuclein - administration & dosage; alpha-Synuclein - deficiency; alpha-Synuclein - pharmacokinetics; alpha-Synuclein - toxicity; Amygdala; Animal models; Animals; Apoptosis; Axonal Transport; Braak hypothesis; Brain Chemistry; Brain research; Dementia; Disease; Dopamine receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Dorsal raphe nucleus; Duodenum - innervation; Duodenum - metabolism; Etiology; Fibrils; gut to brain transmission; Hindbrain; Humans; Injections, Intramuscular; Lewy Bodies - metabolism; Lewy body pathology; Locus coeruleus; Maze Learning; Medical research; Memory Disorders - etiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Neurological; Motor nuclei; motor symptoms; Movement disorders; Muscle, Smooth - innervation; Muscle, Smooth - metabolism; Nesting Behavior - physiology; Neurodegeneration; Neurodegenerative diseases; Neurons; non-motor symptoms; Parkinson's disease; Parkinsonian Disorders - etiology; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - prevention & control; Parkinsonian Disorders - psychology; Pathology; Phosphorylation; pre-formed fibrils; Protein Aggregates; Protein Processing, Post-Translational; Proteins; Pylorus - innervation; Pylorus - metabolism; Raphe nuclei; Rotarod Performance Test; Serine; Substantia nigra; Synuclein; Vagotomy; Vagus nerve; Vagus Nerve - metabolism; α-synuclein; United States > US; Lewy body pathology; vagus nerve; motor symptoms; pre-formed fibrils; Braak hypothesis; neurodegeneration; gut to brain transmission; non-motor symptoms; Parkinson’s disease; α-synuclein
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.05.035

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). [Display omitted] •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 Gut injection of α-synuclein fibrils converts endogenous α-synuclein to a pathologic species that spreads to the brain. This leads to features of Parkinson’s disease, and vagotomy and α-synuclein deficiency prevent the neuropathology and neurobehavioral deficits induced by transmitted pathological α-synuclein.