?-synuclein strains that cause distinct pathologies differentially inhibit proteasome.

ABSTRACT: Abnormal ?-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 ?-synuclein aggregates account for the different pathologies remained unclear. Here, we generated two types of ?-synuclein fibrils from identical monomer and investigated their seeding and propagation ability in mice and primary-cultured neurons. One ?-synuclein fibril induced marked accumulation of phosphorylated ?-synuclein and ubiquitinated protein aggregates, while the other did not, indicating the formation of ?-synuclein two strains. Notably, the former ?-synuclein strain inhibited proteasome activity and co-precipitated with 26S proteasome complex. Further examination indicated that structural differences in the C-terminal region of ?-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 ?-synuclein strains.

SUBMITTER: Suzuki G 

PROVIDER: S-EPMC7406352 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature