Overexpression of quality control proteins reduces prion conversion in prion-infected cells.pdf (2.65 MB)
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Overexpression of quality control proteins reduces prion conversion in prion-infected cells

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journal contribution
posted on 22.11.2022, 23:13 authored by Simrika Thapa, Basant Abdulrahman, Dalia H Abdelaziz, Li Lu, Manel Ben Aissa, Hermann M Schatzl
Prion diseases are fatal infectious neurodegenerative disorders in humans and other animals and are caused by misfolding of the cellular prion protein (PrPC) into the pathological isoform PrPSc These diseases have the potential to transmit within or between species, including zoonotic transmission to humans. Elucidating the molecular and cellular mechanisms underlying prion propagation and transmission is therefore critical for developing molecular strategies for disease intervention. We have shown previously that impaired quality control mechanisms directly influence prion propagation. In this study, we manipulated cellular quality control pathways in vitro by stably and transiently overexpressing selected quality control folding (ERp57) and cargo (VIP36) proteins and investigated the effects of this overexpression on prion propagation. We found that ERp57 or VIP36 overexpression in persistently prion-infected neuroblastoma cells significantly reduces the amount of PrPSc in immunoblots and prion-seeding activity in the real-time quaking-induced conversion (RT-QuIC) assay. Using different cell lines infected with various prion strains confirmed that this effect is not cell type- or prion strain-specific. Moreover, de novo prion infection revealed that the overexpression significantly reduced newly formed PrPSc in acutely infected cells. ERp57-overexpressing cells significantly overcame endoplasmic reticulum stress, as revealed by expression of lower levels of the stress markers BiP and CHOP, accompanied by a decrease in PrP aggregates. Furthermore, application of ERp57-expressing lentiviruses prolonged the survival of prion-infected mice. Taken together, improved cellular quality control via ERp57 or VIP36 overexpression impairs prion propagation and could be utilized as a potential therapeutic strategy.

Funding

National Institutes of Health Grant R01NS076853-01A1 (to H. M. S)

Alberta Innovates - Health Solutions Grant 201300003 (to H. M. S.)

Alberta Innovates - Health Solutions Grant 201600010(to H. M. S.)

201610675 (to S. T.)

20160740 (to B. A.)

Killam Trusts grant (to S. T.)

History

Citation

Thapa, S., Abdulrahman, B., Abdelaziz, D. H., Lu, L., Aissa, M. B.Schatzl, H. M. (2018). Overexpression of quality control proteins reduces prion conversion in prion-infected cells. Journal of Biological Chemistry, 293(41), 16069-16082. https://doi.org/10.1074/jbc.ra118.002754

Publisher

Elsevier BV

Language

en

issn

0021-9258