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

  • Mov Disord. 2023 Oct 5. doi: 10.1002/mds.29620.
Ying Yang  1  2  3 ,  Tessandra Stewart  4 ,  Can Zhang  1 ,  Pan Wang  1  5  6 ,  Zhi Xu  1 ,  Jinghua Jin  1 ,  Yang Huang  3 ,  Zongran Liu  3 ,  Guoyu Lan  3 ,  Xingguang Liang  7 ,  Lifu Sheng  4 ,  Min Shi  4 ,  Zhijian Cai  8 ,  Jing Zhang  1  2  5  6
Affiliations
  • 1. Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang, China.
  • 3. Department of Pathology, Peking University Health Science Center, Beijing, China.
  • 4. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
  • 5. Lingang Laboratory, Shanghai, China.
  • 6. National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, China.
  • 7. Central Laboratory, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 8. School of Basic Medicine, Zhejiang University, Hangzhou, China.
PMID: 37798868 DOI: 10.1002/mds.29620
Abstract

Background: Progressive spreading of α-synuclein via gut-brain axis has been hypothesized in the pathogenesis of Parkinson's Disease (PD). However, the source of seeding-capable α-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 α-synuclein might contribute to PD pathology via a gut-driven pathway and involve GIT microbiota.

Methods: The GIT expression of α-synuclein and the transmission of extracellular vesicles (EVs) derived from erythrocytes/red blood cells (RBCs), with their cargo α-synuclein, to the GIT were explored with various methods, including radioactive labeling of RBC-EVs and direct analysis of the transfer of α-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 α-synuclein genotypes.

Results: This study demonstrated that RBC-EVs can effectively transport α-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 α-synuclein into the GIT was influenced significantly by butyrate and α-synuclein genotypes, which may also affect the GIT microbiome directly.

Conclusion: By demonstrating the transportation of α-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 α-synuclein may impact PD initiation and/or progression. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords
Parkinson's disease; extracellular vesicles; gastrointestinal tract; microbiota; red blood cells; α-synuclein.
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