Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates.

Abstract

In Parkinson's disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via the vagus nerve, to the CNS. Here, we compare, in baboon monkeys, the pathological consequences of either intrastriatal or enteric injection of α-synuclein-containing Lewy body extracts from patients with Parkinson's disease. This study shows that patient-derived α-synuclein aggregates are able to induce nigrostriatal lesions and enteric nervous system pathology after either enteric or striatal injection in a non-human primate model. This finding suggests that the progression of α-synuclein pathology might be either caudo-rostral or rostro-caudal, varying between patients and disease subtypes. In addition, we report that α-synuclein pathological lesions were not found in the vagal nerve in our experimental setting. This study does not support the hypothesis of a transmission of α-synuclein pathology through the vagus nerve and the dorsal motor nucleus of the vagus. Instead, our results suggest a possible systemic mechanism in which the general circulation would act as a route for long-distance bidirectional transmission of endogenous α-synuclein between the enteric and the central nervous systems. Taken together, our study provides invaluable primate data exploring the role of the gut-brain axis in the initiation and propagation of Parkinson's disease pathology and should open the door to the development and testing of new therapeutic approaches aimed at interfering with the development of sporadic Parkinson's disease.

• Authors: Marie-Laure Arotcarena, Sandra Dovero, Alice Prigent, Mathieu Bourdenx, Sandrine Camus, Gregory Porras, Marie-Laure Thiolat, Maddalena Tasselli, Philippe Aubert, Niels Kruse, Brit Mollenhauer, Ines Trigo Damas, Cristina Estrada, Nuria Garcia-Carrillo, Nishant N Vaikath, Omar M A El-Agnaf, Maria Trinidad Herrero, Miquel Vila, Jose A Obeso, Pascal Derkinderen, Benjamin Dehay, Erwan Bezard
• Journal: Brain : a journal of neurology (Brain) Vol. 143 Issue 5 Pg. 1462-1475 (05 01 2020) ISSN: 1460-2156 [Electronic] England
• PMID: 32380543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Chemical References

• alpha-Synuclein

Topics

• Aged
• Animals
• Brain (pathology)
• Enteric Nervous System (drug effects, metabolism, pathology)
• Female
• Humans
• Lewy Bodies (metabolism, pathology)
• Male
• Neuroimmunomodulation (physiology)
• Papio
• Parkinson Disease (physiopathology)
• Vagus Nerve (pathology)
• alpha-Synuclein (administration & dosage, toxicity)