The Parkinson-Associated Toxin Paraquat Shifts Physiological α-Synuclein Tetramers toward Monomers That Can Be Calpain-Truncated and Form Oligomers

Am J Pathol. 2023 May;193(5):520-531. doi: 10.1016/j.ajpath.2023.01.010. Epub 2023 Feb 9.

Abstract

Abnormal aggregation of α-synuclein (αS) is thought to initiate neuronal dysfunction and death in Parkinson disease (PD). In addition to higher-molecular-weight, oligomeric, and polymeric forms of αS associated with neurotoxicity and disease, recent findings indicate the occurrence of physiological tetrameric assemblies in healthy neurons in culture and in brain. Herein, the PD-associated neurotoxin paraquat reduced physiological tetramers and led to calpain-truncated monomers and an approximately 70-kDa apparent oligomer different in size from physiological αS multimers. These truncated and oligomeric forms could also be generated by calpain cleavage of pure, recombinant human αS in vitro. Moreover, they were detected in the brains of tetramer-abrogating, E46K-amplified (3K) mice that model PD. These results indicate that paraquat triggers membrane damage and aberrant calpain activity that can induce a pathologic shift of tetramers toward an excess of full-length and truncated monomers, the accumulation of αS oligomers, and insoluble cytoplasmic αS puncta. The findings suggest that an environmental precipitant of PD can alter αS tetramer/monomer equilibrium, as already shown for several genetically caused forms of PD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calpain
  • Humans
  • Mice
  • Paraquat / toxicity
  • Parkinson Disease*
  • alpha-Synuclein* / toxicity

Substances

  • alpha-Synuclein
  • Calpain
  • Paraquat