Epigenetic inactivation of the autophagy–lysosomal system in appendix in Parkinson’s disease

Juozas Gordevicius (), Peipei Li, Lee L. Marshall, Bryan A. Killinger, Sean Lang, Elizabeth Ensink, Nathan C. Kuhn, Wei Cui, Nazia Maroof, Roberta Lauria, Christina Rueb, Juliane Siebourg-Polster, Pierre Maliver, Jared Lamp, Irving Vega, Fredric P. Manfredsson, Markus Britschgi and Viviane Labrie
Additional contact information
Juozas Gordevicius: Van Andel Institute
Peipei Li: Van Andel Institute
Lee L. Marshall: Van Andel Institute
Bryan A. Killinger: Van Andel Institute
Sean Lang: Van Andel Institute
Elizabeth Ensink: Van Andel Institute
Nathan C. Kuhn: Michigan State University
Wei Cui: Van Andel Institute
Nazia Maroof: Neuroscience Discovery, Roche Innovation Center, Basel, F. Hoffmann-La Roche Ltd
Roberta Lauria: Neuroscience Discovery, Roche Innovation Center, Basel, F. Hoffmann-La Roche Ltd
Christina Rueb: Neuroscience Discovery, Roche Innovation Center, Basel, F. Hoffmann-La Roche Ltd
Juliane Siebourg-Polster: Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd
Pierre Maliver: Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd
Jared Lamp: Michigan State University
Irving Vega: Michigan State University
Fredric P. Manfredsson: Michigan State University
Markus Britschgi: Neuroscience Discovery, Roche Innovation Center, Basel, F. Hoffmann-La Roche Ltd
Viviane Labrie: Van Andel Institute

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson’s disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD.

Date: 2021
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DOI: 10.1038/s41467-021-25474-x

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