An archaeal compound as a driver of Parkinson’s disease pathogenesis

Type Article
Acceptance Date 2022-07-26 IN PRESS
Language English
Author(s) Trezzi Jean-Pierre1, 2, Aho VelmaORCID1, Jäger ChristianORCID1, Schade SebastianORCID3, 4, Janzen Annette5, Hickl Oskar1, Kunath Benoit1, Thomas Mélanie1, 6, Schmit Kristopher1, 6, Garcia Pierre1, 6, Sciortino Alessia1, 6, Martin-Gallausiaux Camille1, Halder RashiORCID1, Huarte Oihane Uriarte1, 6, Heurtaux Tony6, 7, Heins-Marroquin Ursula1, Gomez-Giro Gemma1, Weidenbach Katrin8, Delacour Léa1, Laczny Cédric1, Novikova Polina1, Ramiro-Garcia JavierORCID1, Singh Randolph1, 9, Andújar Begoña Talavera1, Lebrun Laura1, Daujeumont Annegrait1, Habier Janine1, Dong Xiangyi1, Gavotto Floriane1, Heintz-Buschart AnnaORCID10, Schneider Jochen1, 11, Jehmlich NicoORCID12, von Bergen MartinORCID12, Schymanski EmmaORCID1, Schmitz RuthORCID8, Schwamborn JensORCID1, Glaab EnricoORCID1, Linster CaroleORCID1, Kitami Toshimori13, Buttini Manuel1, 6, May PatrickORCID1, Trenkwalder Claudia4, 14, Oertel Wolfgang5, Mollenhauer Brit4, 5, Wilmes Paul1, 7
Affiliation(s) 1 : Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
2 : Integrated Biobank of Luxembourg, Luxembourg Institute of Health, Dudelange, Luxembourg
3 : Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
4 : Paracelsus-Elena-Klinik, Kassel, Germany
5 : Department of Neurology, Philipps-University Marburg, Marburg, Germany
6 : Luxembourg Center of Neuropathology (LCNP), Dudelange, Luxembourg
7 : Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
8 : Institute for General Microbiology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
9 : Unité Contamination Chimique des Ecosystèmes Marins, IFREMER (Institut Français de Recherche pour l’Exploitation de la Mer), Nantes, France
10 : Biosystems Data Analysis, Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, The Netherlands
11 : Departments of Internal Medicine and Psychiatry and Psychotherapy, Saarland University Medical Center at Homburg/Saar, Homburg, Germany
12 : Helmholtz-Zentrum für Umweltforschung – UFZ GmbH, Department Molekulare Systembiologie, Leipzig, Germany
13 : RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
14 : Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
Source Under Review at Nature Portfolio. (Research Square Platform LLC) In Press
DOI 10.21203/
Note This is a preprint ; it has not been peer reviewed by a journal

Patients with Parkinson’s disease (PD) exhibit differences in their gut microbiomes compared to healthy individuals. Although differences have most commonly been described in the abundances of bacterial taxa, changes to viral and archaeal populations have also been observed. Mechanistic links between gut microbes and PD pathogenesis remain elusive but could involve molecules that promote α-synuclein aggregation. Here, we show that 2-hydroxypyridine (2-HP) represents a key molecule for the pathogenesis of PD. We observe significantly elevated 2-HP levels in faecal samples from patients with PD or its prodrome, idiopathic REM sleep behaviour disorder (iRBD), compared to healthy controls. 2-HP is correlated with the archaeal species Methanobrevibacter smithii and with genes involved in methane metabolism, and it is detectable in isolate cultures of M. smithii. We demonstrate that 2-HP is selectively toxic to transgenic α-synuclein overexpressing yeast and increases α-synuclein aggregation in a yeast model as well as in human induced pluripotent stem cell derived enteric neurons. It also exacerbates PD-related motor symptoms, α-synuclein aggregation, and striatal degeneration when injected intrastriatally in transgenic mice overexpressing human α-synuclein. Our results highlight the effect of an archaeal molecule in relation to the gut-brain axis, which is critical for the diagnosis, prognosis, and treatment of PD.

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Trezzi Jean-Pierre, Aho Velma, Jäger Christian, Schade Sebastian, Janzen Annette, Hickl Oskar, Kunath Benoit, Thomas Mélanie, Schmit Kristopher, Garcia Pierre, Sciortino Alessia, Martin-Gallausiaux Camille, Halder Rashi, Huarte Oihane Uriarte, Heurtaux Tony, Heins-Marroquin Ursula, Gomez-Giro Gemma, Weidenbach Katrin, Delacour Léa, Laczny Cédric, Novikova Polina, Ramiro-Garcia Javier, Singh Randolph, Andújar Begoña Talavera, Lebrun Laura, Daujeumont Annegrait, Habier Janine, Dong Xiangyi, Gavotto Floriane, Heintz-Buschart Anna, Schneider Jochen, Jehmlich Nico, von Bergen Martin, Schymanski Emma, Schmitz Ruth, Schwamborn Jens, Glaab Enrico, Linster Carole, Kitami Toshimori, Buttini Manuel, May Patrick, Trenkwalder Claudia, Oertel Wolfgang, Mollenhauer Brit, Wilmes Paul An archaeal compound as a driver of Parkinson’s disease pathogenesis. Under Review at Nature Portfolio. IN PRESS. Publisher's official version : , Open Access version :