Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates

Mathieu Bourdenx (1) , Aurélien Nioche (1) , Sandra Dovero (1) , Marie-Laure Arotcarena (1) , Sandrine M. J. Camus (1) , Gregory Porras (1) , Marie-Laure Thiolat (1) , Nicolas P. Rougier (2) , Alice Prigent (3) , Philippe Aubert (3) , Sylvain Bohic (4) , Christophe Sandt (5) , Florent Laferrière (1) , Evelyne Doudnikoff (1) , Niels Kruse (6) , Brit Mollenhauer (6) , Salvatore Novello (7) , Michele Morari (7) , Thierry Leste-Lasserre (8) , Ines Trigo Damas (9) , Michel Goillandeau (1) , Celine Perier (9) , Cristina Estrada (10) , Nuria García Carrillo (10) , Ariadna Recasens (9) , Nishant Narayanan Vaikath (11) , Omar El Agnaf (11) , Maria Trinidad Herrero (10) , Pascal Derkinderen (8) , Miquel Vila (9) , Jose A Obeso (9) , Benjamin Dehay (1) , Erwan Bezard (1)

1 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
2 Mnemosyne - Mnemonic Synergy
3 Neuropathies du système nerveux entérique et pathologies digestives : implication des cellules gliales entériques
4 ESRF - European Synchrotron Radiation Facility
5 SSOLEIL - Synchrotron SOLEIL
6 UMG - University Medical Center Göttingen
7 UniFE - Università degli Studi di Ferrara = University of Ferrara
8 INSERM - Institut National de la Santé et de la Recherche Médicale
9 ISC - Instituto de Salud Carlos III [Madrid]
10 Universidad de Murcia
11 HBKU - Hamad Bin Khalifa University

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates (termed ‘Lewy bodies’), is a well-established characteristic of Parkinson’s disease. Much evidence, accumulated from multiple experimental models has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.

Domaines: Neurosciences

Mathieu Bourdenx, Aurélien Nioche, Sandra Dovero, Marie-Laure Arotcarena, Sandrine M. J. Camus, et al.. Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates. Science Advances , 2020, 6 (20), pp.eaaz9165. ⟨10.1126/sciadv.aaz9165⟩. ⟨hal-02611441⟩