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An archaeal compound as a driver of Parkinson’s disease pathogenesis
- Source :
- Under Review at Nature Portfolio. (Research Square Platform LLC) In Press
- Publication Year :
- 2022
-
Abstract
- 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.
- Subjects :
- Environmental sciences & ecology [F08] [Life sciences]
Sciences de l'environnement & écologie [F08] [Sciences du vivant]
Microbiologie [F11] [Sciences du vivant]
Neurologie [D14] [Sciences de la santé humaine]
Neurology [D14] [Human health sciences]
Microbiology [F11] [Life sciences]
Genetics & genetic processes [F10] [Life sciences]
Biochemistry, biophysics & molecular biology [F05] [Life sciences]
Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant]
Génétique & processus génétiques [F10] [Sciences du vivant]
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Under Review at Nature Portfolio. (Research Square Platform LLC) In Press
- Accession number :
- edsair.doi.dedup.....00f522cd65c9b0ae0a2cc5a97d6a362a