Differential seeding and propagating efficiency of α-synuclein strains generated in different conditions

Research output: Contribution to journalArticle

Abstract

Background: Accumulation of alpha-synuclein (α-syn) is a main pathological hallmark of Parkinson’s and related diseases, which are collectively known as synucleinopathies. Growing evidence has supported that the same protein can induce remarkably distinct pathological progresses and disease phenotypes, suggesting the existence of strain difference among α-syn fibrils. Previous studies have shown that α-syn pathology can propagate from the peripheral nervous system (PNS) to the central nervous system (CNS) in a “prion-like” manner. However, the difference of the propagation potency from the periphery to CNS among different α-syn strains remains unknown and the effect of different generation processes of these strains on the potency of seeding and propagation remains to be revealed in more detail. Methods: Three strains of preformed α-syn fibrils (PFFs) were generated in different buffer conditions which varied in pH and ionic concentrations. The α-syn PFFs were intramuscularly (IM) injected into a novel bacterial artificial chromosome (BAC) transgenic mouse line that expresses wild-type human α-syn, and the efficiency of seeding and propagation of these PFFs from the PNS to the CNS was evaluated. Results: The three strains of α-syn PFFs triggered distinct propagation patterns. The fibrils generated in mildly acidic buffer led to the most severe α-syn pathology, degeneration of motor neurons and microgliosis in the spinal cord. Conclusions: The different α-syn conformers generated in different conditions exhibited strain-specific pathology and propagation patterns from the periphery to the CNS, which further supports the view that α-syn strains may be responsible for the heterogeneity of pathological features and disease progresses among synucleinopathies.

Details

Authors
Organisations
External organisations
  • Northeastern University
  • China Medical University, Shenyang
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • Parkinson’s disease, Prion-like propagation, Strains, α-Synuclein
Original languageEnglish
Article number20
JournalTranslational Neurodegeneration
Volume10
Publication statusPublished - 2021 Dec
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

Funding Information: Financial supports of JYL lab by the National Key Research and Development Program of China (2018YFA0108500), the National Natural Science Foundation (81430025, 81701265, 31800898, U1801681), and the Key Field Research Development Program of Gungdong Province (2018B030337001). Financial supports of JYL lab by the Swedish Research Council (521–2014-3257, 2019–01551), EU-JPND (aSynProtec) and EU-JPND (REfrAME), EU H2020-MSCA-ITN-2016 (Syndegen), the Strong Research Environment MultiPark (Multidisciplinary research on Parkinson’s disease), Parkinsonfonden and Olle Engkvist Byggmästare Foundation. DL was supported by China Scholarship Council. Open Access funding provided by Lund University. Funding Information: We thank Sheng Yang (College of Life and Health Sciences, Northeastern University, China) for the help of behavioral tests. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.