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

ELife
Genjiro SuzukiMasato Hasegawa

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.

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Citations

Nov 21, 2020·International Journal of Molecular Sciences·Dominika FricovaAlzbeta Kralova Trancikova
Jul 3, 2021·Biomolecules·Simon Oliver HoppeCarmen Nussbaum-Krammer
Jun 15, 2021·Frontiers in Cell and Developmental Biology·Bipul RayMeena Kishore Sakharkar
Oct 26, 2021·Experimental Neurology·Eva M SzegöBjörn H Falkenburger

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Methods Mentioned

BETA
glycosylation
Transfer electron microscopy
Dot blot
dot-blot

Software Mentioned

EZR

Related Concepts

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Alpha-Synuclein Aggregation (MDS)

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.

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