Objective: The prototypic synucleinopathy Parkinson’s disease (PD) is hypothesized to spread out from the enteric nervous system (i.e. the gut) via the vagal nerve up to the central nervous system (Lionnet et al., 2017). Such popular hypothesis is supported by indirect clinical evidences and by experimental data showing gut-to-brain transfer of synucleinopathy using either viral vector delivery of synuclein or recombinant synuclein preformed fibrils.

Background: The aim of this study was to test the alternate hypothesis that synucleinopathy can indeed develop upward but also downward, i.e. from the gut to the brain but also from the brain to the gut.

Methods: To this end, we used our primate model of synucleinopathy obtained with administration of α-synuclein species contained in PD-derived Lewy bodies (LB) (Recasens et al., 2014). We examined in non-human primates, (i) if LB administration in the ventral wall of the stomach (n=5) leads to central nervous α-synuclein aggregation and possibly nigrostriatal degeneration and (ii) if LB administration in the striatum (n=6) might lead to synucleinopathy into the enteric nervous system. Two years after injection, extensive analysis was performed to assess qualitatively, quantitatively and spatially in the whole brain and in the enteric nervous system the extent and pattern of lesion as well as the occurrence of synucleinopathy using both biochemical and histochemical procedures.

Results: Enteric injection of LB in non-human primates results in enteric nervous system pathology and nigrostriatal lesion in keeping with the well-accepted hypothesis. However, striatum LB-injected animals, in addition to the expected nigrostriatal degeneration, showed also enteric ner¬vous system pathology at the stomach level.

Conclusions: This study establishes that α-synuclein species might move up and down the neural axis in non-human primates questioning (i) the hypothesis of a peripheral origin of synucleinopathies (ii) and the specificity of enteric nervous system as biomarker of early/presymptomatic PD.

References: [1] A. Lionnet, L. Leclair-Visonneau, M. Neunlist, S. Murayama, M. Takao, C.H. Adler, P. Derkinderen, T.G. Beach, Does Parkinson’s disease start in the gut?, Acta Neuropathol, 135 (2018) 1-12. [2] A. Recasens, B. Dehay, J. Bove, I. Carballo-Carbajal, S. Dovero, A. Perez-Villalba, P.O. Fernagut, J. Blesa, A. Parent, C. Perier, I. Farinas, J.A. Obeso, E. Bezard, M. Vila, Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys, Ann Neurol, 75 (2014) 351-362.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/bidirectional-gut-to-brain-and-brain-to-gut-propagation-of-%ce%b1-synuclein-pathology-in-non-human-primates/