The Influence of Bacterial Amyloid on Alpha Synuclein (AS) Misfolding in the Rat (P4.334)

OBJECTIVE. To uncover the initiating factors responsible for protein misfolding and neuroinflammation in Parkinson’s disease (PD) we have studied the hypothesis that exposure to bacterial amyloid in the gut enhances AS misfolding and inflammation in gut and brain neurons. BACKGROUND. Recent studies have shown that misfolded AS and related proteins (Aβ, Tau, TDP43) have prion-like properties that involve autocatalytic noncovalent, self-propagating, nucleation dependent production of β-pleated sheet structures which are transmitted between organisms, as well as between body regions. The largest opportunity for exposure of humans to foreign antigens is in the gut, which contains 1-2 Kg of bacteria. These commensal organisms (the microbiota) include bacteria that make functional amyloid proteins. METHODS. Aged Fischer 344 male rats which develop AS deposits in gut neurons with age (~24 months) were exposed orally every week for 2-3 months to 3 materials: 1). Mutant E. coli unable to produce the protein curli (n=9); 2). Wild type E. coli making the extracellular amyloid protein curli, (n=11); or 3). Vehicle alone (n=13). RESULTS. Rats exposed to bacteria producing curli had more neuronal AS deposition in neurons in both gut and brain (striatum and hippocampus), and also had more microgliosis in brain (neocortex, hippocampus, and striatum) than rats exposed to either mutant bacteria unable to synthesize curli or to vehicle alone. There were no differences among the groups in regards to survival, body weight, inflammation in the mouth, retina, kidneys or gut epithelia, or circulating cytokine levels. Our findings do not appear to be caused by T cell activation by bacterial amyloid. CONCLUSIONS. These results suggest that bacterial amyloid may be working as a trigger to initiate AS aggregation through cross-seeding and enhance immune responses to AS. The role of the microbiota in neurodegenerative disorders deserves further investigation. Supported by the MJ fox Foundation. Disclosure: Dr. Friedland has nothing to disclose. Dr. Rane has nothing to disclose. Dr. Gozal has nothing to disclose. Dr. Jin has nothing to disclose. Dr. Jagadapillai1 has nothing to disclose. Dr. Roberts has nothing to disclose. Dr. Liu has nothing to disclose. Dr. Masliah has nothing to disclose. Dr. Stribinskis has nothing to disclose.