Erythrocytic -Synuclein and the Gut Microbiome: Kindling of the Gut-Brain Axis in Parkinson's Disease

Background: Progressive spreading of alpha-synuclein via gut-brain axis has been hypothesized in the pathogenesis of Parkinson's disease (PD). However, the source of seeding-capable alpha-synuclein in the gastrointestinal tract (GIT) has not been fully investigated. Additionally, the mechanism by which the GIT microbiome contributes to PD pathogenesis remains to be characterized.Objectives: We aimed to investigate whether blood-derived alpha-synuclein might contribute to PD pathology via a gut-driven pathway and involve GIT microbiota.Methods: The GIT expression of alpha-synuclein and the transmission of extracellular vesicles (EVs) derived from erythrocytes/red blood cells (RBCs), with their cargo alpha-synuclein, to the GIT were explored with various methods, including radioactive labeling of RBC-EVs and direct analysis of the transfer of alpha-synuclein protein. The potential role of microbiota on the EVs transmission was further investigated by administering butyrate, the short-chain fatty acids produced by gut microbiota and studying mice with different alpha-synuclein genotypes.Results: This study demonstrated that RBC-EVs can effectively transport alpha-synuclein to the GIT in a region-dependent manner, along with variations closely associated with regional differences in the expression of gut-vascular barrier markers. The investigation further revealed that the infiltration of alpha-synuclein into the GIT was influenced significantly by butyrate and alpha-synuclein genotypes, which may also affect the GIT microbiome directly.Conclusion: By demonstrating the transportation of alpha-synuclein through RBC-EVs to the GIT, and its potential association with gut-vascular barrier markers and gut microbiome, this work highlights a potential mechanism by which RBC alpha-synuclein may impact PD initiation and/or progression. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.