Molecular Mediation of Prion-like α-Synuclein Fibrillation from Toxic PFFs to Nontoxic Species

Longgang Jia, Yuqing Liu, Wenliang Wang, Ying Wang, Haiqing Liu, Fufeng Liu, Rong Chen, Valina L. Dawson, Ted M. Dawson, Fuping Lu, Lei Liu, Yanping Wang, Xiaobo Mao

Research output: Contribution to journalArticlepeer-review

Abstract

Braak's theory described Parkinson's disease (PD) progression as prion-like α-synuclein (αSyn) spreading, which fundamentally subverts the understanding of pathogenesis. The pathological αSyn spreading pathway includes uptake, propagation, and release. However, the previous disease models were limitedly focusing on amyloid propagation/aggregation, which significantly impedes the mechanism exploration in spreading pathways and related therapeutic development. The spreading model can be achieved using recombinant αSyn preformed fibrils (PFFs), which seeds endogenous αSyn monomer to aggregation and causes substantial pathology and neurotoxicity. Here, we determined that dihydromyricetin (DHM), a natural flavonoid extracted from Ampelopsis grossedentata, can promote the fibrillization of prion-like PFF and induce propagation to form a distinct strain. Furthermore, administration of DHM significantly reduced prion-like PFF-induced propagation and neurotoxicity. The discovery of inducing infectious and neurotoxic PFF to a nontoxic strain resulting in neuron protection via promoting the fibrillization of PFF rather than inhibiting advances the understanding of the prion-like spreading mechanism and helps in developing treatments against PD and related α-synucleinopathies.

Original languageEnglish (US)
Pages (from-to)6096-6102
Number of pages7
JournalACS Applied Bio Materials
Volume3
Issue number9
DOIs
StatePublished - Sep 21 2020

Keywords

  • Parkinson's disease
  • dihydromyricetin
  • primary neurons
  • spreading
  • α-synuclein preformed fibrils

ASJC Scopus subject areas

  • Biomaterials
  • Chemistry(all)
  • Biomedical Engineering
  • Biochemistry, medical

Fingerprint Dive into the research topics of 'Molecular Mediation of Prion-like α-Synuclein Fibrillation from Toxic PFFs to Nontoxic Species'. Together they form a unique fingerprint.

Cite this