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

• Published in: Nature communications Vol. 12; no. 1; p. 5134
• Main Authors: Gordevicius, Juozas, Li, Peipei, Marshall, Lee L., Killinger, Bryan A., Lang, Sean, Ensink, Elizabeth, Kuhn, Nathan C., Cui, Wei, Maroof, Nazia, Lauria, Roberta, Rueb, Christina, Siebourg-Polster, Juliane, Maliver, Pierre, Lamp, Jared, Vega, Irving, Manfredsson, Fredric P., Britschgi, Markus, Labrie, Viviane
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.08.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45/15; 45/23; 45/91; 631/378; 631/378/1689/1718; 631/378/2584; 82/58; Abnormalities; alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Appendix - chemistry; Appendix - metabolism; Autophagy; Brain - metabolism; Brain - pathology; Deoxyribonucleic acid; Disruption; DNA; DNA Methylation; DNA sequencing; Epigenesis, Genetic; Epigenetics; Female; Gastrointestinal system; Gastrointestinal tract; Genes; Humanities and Social Sciences; Humans; Inactivation; Lysosomes - chemistry; Lysosomes - genetics; Lysosomes - metabolism; Male; Mice; Mice, Inbred C57BL; Movement disorders; multidisciplinary; Neurodegenerative diseases; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathology; Phagocytosis; Protein Aggregates; Science; Science (multidisciplinary); Synuclein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25474-x

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. Dysfunction of the gastrointestinal system, and to the autophagy lysososmal pathway (ALP) have been reported in Parkinson’s disease. Here the authors report epigenetic disruption of ALP related genes in the appendix of individuals with Parkinson’s disease.