Explore the vast range of titles available.

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.

Intraneuronal α-synuclein accumulation is key in Parkinson's disease (PD) pathogenesis. The pathogenic process is suggested to begin in the enteric nervous system and propagate into the brain already decades before diagnosis of PD. In some patients, colitis might play a critical role in this process. Here we demonstrate that patients with inflammatory bowel disease exhibit α-synuclein accumulation in the colon and that experimental colitis triggers α-synuclein accumulation in certain enteric nerves of mice. The type and degree of experimental inflammation modulates the extent of colonic α-synuclein accumulation and macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbates the accumulation of aggregated phospho-Serine 129 α-synuclein in the midbrain (including the substantia nigra), in 21- but not 9-month-old α-synuclein transgenic mice. This is accompanied by loss of tyrosine hydroxylase-immunoreactive nigral neurons. Our data suggest that intestinal inflammation might play a critical role in the initiation and progression of PD. Footnotes * Edited and updated entire manuscript (text, new references, figures) for submission to another journal. Content remains the same.