Cytotoxicity of α-synuclein amyloid fibrils generated with phage chaperonin OBP

Pozdyshev, D.V.; Leisi, E.V.; Muronetz, V.I.; Golyshev, S.A.; Kurochkina, L.P.

Авторы: Pozdyshev Denis V., Leisi Evgeniia V., Muronetz Vladimir I., Golyshev Sergei A., Kurochkina Lidia P.
Журнал: Biochemical and Biophysical Research Communications
Том: 742
Год издания: 2025
Издательство: Academic Press
Местоположение издательства: United States
Номер статьи: 151127
DOI: 10.1016/j.bbrc.2024.151127
Аннотация: Chaperonins are known to be important players in the conversion of amyloidogenic proteins into amyloid precursors in a variety of neurodegenerative diseases. However, the mechanisms of their action is still poorly understood. In this work, we used a single-ring chaperonin of the bacteriophage OBP, which functions in an ATP-dependent manner but has a simpler structure than other chaperonins. The effect of the chaperonin OBP on the conversion of human α-synuclein mutant A53T into amyloid was studied and the cytotoxicity of the formed fibrils was investigated. The phage chaperonin OBP was expressed in HEK293T cells together with the human α-synuclein mutant A53T. Both proteins showed a diffuse distribution within the cell cytoplasm as determined by fluorescence microscopy using specific antibodies. Separate and co-expression of the two proteins did not result in the formation of distinguishable protein aggregates in the cells, nor did it have any effect on cell viability. However, the co-expression of chaperonin and α-synuclein did result in the appearance of some dimeric and oligomeric forms of α-synuclein in the insoluble fraction of the cell lysate. It can therefore be concluded that chaperonin OBP stimulates the amyloid transformation of α-synuclein A53T when both proteins are co-expressed in eukaryotic cells. A comparison of the cytotoxicity of mutant α-synuclein amyloid forms obtained in vitro, both during spontaneous fibrillation and with the participation of the chaperonin OBP, showed that the maximum effect on HEK293T and SH-SY5Y cells, resulting in the death of more than 50 % of the population, was exerted by α-synuclein fibrils formed under chaperonin action in the presence of ATP. In the context of recent data on the spread of amyloid α-synuclein from the gut to the brain, the role of phage chaperonins in the pathological aggregation of amyloidogenic proteins in the human body and the potential use of the OBP chaperonin in cellular models of synucleinopathies are discussed.
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Cytotoxicity of α-synuclein amyloid fibrils generated with phage chaperonin OBPстатья

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