GSE135746
Epigenetic inactivation of the autophagy-lysosomal system in the Parkinson's disease appendix (5: OFB)
The gastrointestinal tract may be a site of origin for a-synuclein (a-syn) pathology in idiopathic Parkinson's disease (PD), and an abundance of aggregated a-syn has recently been demonstrated in both the healthy and PD appendix. However, the molecular changes that enable gut a-syn aggregates to contribute to the development and progression of PD remain unclear. Here, our deep-sequencing of DNA methylation changes at 521 autophagy-lysosomal pathway (ALP) genes in the human appendix and brain in PD and healthy controls indicates a pattern of widespread hypermethylation in the PD appendix that is recapitulated in the PD brain. There is significant overlap in the individual ALP genes affected across the PD appendix and brain, with lysosomal genes specifically downregulated in both regions. Healthy epigenetic aging, which involves a hypermethylation of macroautophagy and selective autophagy genes in the appendix and brain, is disrupted in both areas in PD. In mice, DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by the presence of a-syn pathology. DNA methylation changes at ALP genes induced by a-synucleinopathy are significantly associated with the ALP abnormalities observed in the PD appendix, specifically involving lysosomal genes. Our work, which constitutes an in-depth, unbiased investigation of epigenetic changes in the ALP of the PD gut and brain, identifies the epigenetic misregulation of the ALP, especially a downregulation of lysosomal genes, as a potential culprit for the initiation and spread of a-syn pathology in idiopathic PD. Overall design: DNA methylation at 521 known ALP genes and surrounding genomic area (± 300 kb) was profiled in the PD and control olfactory bulb