2. Academic Validation
  3. Erythrocytic α-Synuclein and the Gut Microbiome: Kindling of the Gut-Brain Axis in Parkinson's Disease

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

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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