α-synuclein strains that cause distinct pathologies differentially inhibit proteasome

Elife. 2020 Jul 22;9:e56825. doi: 10.7554/eLife.56825.

Abstract

Abnormal α-synuclein aggregation has been implicated in several diseases and is known to spread in a prion-like manner. There is a relationship between protein aggregate structure (strain) and clinical phenotype in prion diseases, however, whether differences in the strains of α-synuclein aggregates account for the different pathologies remained unclear. Here, we generated two types of α-synuclein fibrils from identical monomer and investigated their seeding and propagation ability in mice and primary-cultured neurons. One α-synuclein fibril induced marked accumulation of phosphorylated α-synuclein and ubiquitinated protein aggregates, while the other did not, indicating the formation of α-synuclein two strains. Notably, the former α-synuclein strain inhibited proteasome activity and co-precipitated with 26S proteasome complex. Further examination indicated that structural differences in the C-terminal region of α-synuclein strains lead to different effects on proteasome activity. These results provide a possible molecular mechanism to account for the different pathologies induced by different α-synuclein strains.

Keywords: mouse; neuroscience; prion; proteasome; strain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fungal Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / pathology*
  • Proteasome Endopeptidase Complex / metabolism*
  • Saccharomyces cerevisiae / chemistry
  • alpha-Synuclein / metabolism*

Substances

  • Fungal Proteins
  • alpha-Synuclein
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease