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bioRxiv · 10.1101/2020.03.19.999086

α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome

Suzuki, G.·Imura, S.·Hosokawa, M.·Katsumata, R.·Nonaka, T.·Hisanaga, S.-I.·Saeki, Y.·Hasegawa, M.
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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.

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Suzuki, G., Imura, S., Hosokawa, M., Katsumata, R., Nonaka, T., Hisanaga, S.-I., Saeki, Y., Hasegawa, M.. 2020-03-20. α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome. https://doi.org/10.1101/2020.03.19.999086

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