Copper and iron ions accelerate the prion-like propagation of α-synuclein: A vicious cycle in Parkinson's disease

Yang Li, Chen Yang, Shilin Wang, Dong Yang, Yu Zhang, Li Xu, Liang Ma, Jiaojiao Zheng, Robert B. Petersen, Ling Zheng, Hong Chen, Kun Huang

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Protein fibrils drive the onset and progression of many diseases in a prion-like manner, i.e. they transcellular propagate through the extracellular space to health cells to initiate toxic aggregation as seeds. The conversion of native α-synuclein into filamentous aggregates in Lewy bodies is a hallmark of Parkinson's disease (PD). Copper and iron ions accumulate in PD brains, however, whether they influence the prion-like propagation of α-synuclein remain unclear. Here, we reported that copper/iron ions accelerate prion-like propagation of α-synuclein fibrils by promoting cellular internalization of α-synuclein fibrils, intracellular α-synuclein aggregation and the subsequent release of mature fibrils to the extracellular space to induce further propagation. Mechanistically, copper/iron ions enhanced α-synuclein fibrils internalization was mediated by negatively charged membrane heparan sulfate proteoglycans (HSPGs). α-Synuclein fibrils formed in the presence of copper/iron ions were more cytotoxic, causing increased ROS production, cell apoptosis, and shortened the lifespan of a C. elegans PD model overexpressing human α-synuclein. Notably, these deleterious effects were ameliorated by two clinically used chelators, triethylenetetramine and deferiprone. Together, our results suggest a new role for heavy metal ions, e.g. copper and iron, in the pathogenesis of PD through accelerating prion-like propagation of α-synuclein fibrils.

Original languageEnglish
Pages (from-to)562-573
Number of pages12
JournalInternational Journal of Biological Macromolecules
Volume163
DOIs
StatePublished - Nov 15 2020

Keywords

  • Copper/iron ions
  • Heparan sulfate proteoglycans (HSPGs)
  • Metal chelators
  • Parkinson's disease
  • Prion-like propagation
  • α-Synuclein

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