Gut Protein Acetylation: A Potential Trigger of Autoimmune Responses via Extracellular Vesicles in Parkinson’s Disease
Background
Parkinson’s disease (PD) is a common neurodegenerative disorder. While motor symptoms are the distinctive clinical features, non-motor symptoms, particularly gastrointestinal (GI) disorders, are prevalent and can precede motor symptoms by years. Recent research suggests that in some PD patients, the pathology begins in the gut and progresses to the brain. PD is also associated with immune alterations, including autoimmune features. Notably, autoantibodies against protein acetylation (PA) have been linked to autoimmune diseases, with a suspected origin in the gut. We hypothesize that PA occurs in the gut, leading to the formation of anti-acetylated protein antibodies (AAPAs), which may be associated with PD. Additionally, extracellular vesicles (EVs) may transport acetylated proteins from the gut, triggering autoimmune responses.
Methods
PA levels were determined using immunodot-blot in fecal samples from 20 PD and 19 healthy individuals, as well as in intestinal contents from transgenic PD Thy1-SNCA mice and non-transgenic controls. Serum AAPA levels in 12 PD patients were assessed using ELISA. PA in isolated EVs from human feces was evaluated via Western blot.
Results
PA levels increased in small intestine-derived contents in PD mice. Interestingly, PA levels decreased in fecal contents from PD mice and patients. Acetylated proteins were enriched in EVs isolated from human feces. Serum analysis revealed high AAPA levels in up to 58% of PD patients.
Conclusion
Our findings demonstrate PA presence in the GI content of PD mice and in patient feces, and suggest the small intestine as a primary site for PA. The high AAPA levels in some PD patients indicate the involvement of the PA-to-AAPA cascade in autoimmune responses in PD. PA enrichment in EVs suggests that EVs may transport acetylated proteins from the gut, triggering AAPA production. These results lay the groundwork for further studies on PA in larger PD cohorts.
Keywords
Protein acetylation; anti-acetylated protein antibodies; Parkinson’s disease; fecal extracellular vesicles
Funding
DFG KFO 5025; IZKF Erlangen (P128); Forschungsstiftung Medizin am Universitätsklinikum
Authors
Verena Schmitt1, Martin Weidenfeller1, Ippei Miyagawa2, Birthe Gericke3, Martin Regensburger1, Franz Marxreiter1, Franziska Richter3, Mario M. Zaiss2, Jürgen Winkler1, Wei Xiang1 (Corresponding Author: wei.xiang[at]fau[dot]de)