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RNA modulates aggregation of the recombinant mammalian prion protein by direct interaction
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.ORCID iD: 0000-0003-4448-6447
Fiocruz MS, Biomanguinhos, Inst Tecnol Imunobiol, BR-21040900 Rio De Janeiro, Brazil.
Univ Fed Rio de Janeiro, Fac Farm, BR-21941902 Rio De Janeiro, Brazil.ORCID iD: 0000-0003-4278-212X
Univ Fed Rio de Janeiro, Fac Farm, BR-21941902 Rio De Janeiro, Brazil;NIAID, Lab Persistent Viral Dis, Rocky Mt Labs, NIH, Hamilton, MT USA.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 12406Article in journal (Refereed) Published
Abstract [en]

Recent studies have proposed that nucleic acids act as potential cofactors for protein aggregation and prionogenesis. By means of sedimentation, transmission electron microscopy, circular dichroism, static and dynamic light scattering, we have studied how RNA can influence the aggregation of the murine recombinant prion protein (rPrP). We find that RNA, independent of its sequence, source and size, modulates rPrP aggregation in a bimodal fashion, affecting both the extent and the rate of rPrP aggregation in a concentration dependent manner. Analogous to RNA-induced liquid-liquid phase transitions observed for other proteins implicated in neurodegenerative diseases, high protein to RNA ratios stimulate rPrP aggregation, while low ratios suppress it. However, the latter scenario also promotes formation of soluble oligomeric aggregates capable of seeding de novo rPrP aggregation. Furthermore, RNA co-aggregates with rPrP and thereby gains partial protection from RNase digestion. Our results also indicate that rPrP interacts with the RNAs with its N-terminus. In summary, this study elucidates the proposed adjuvant role of RNA in prion protein aggregation and propagation, and thus advocates an auxiliary role of the nucleic acids in protein aggregation in general.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 9, article id 12406
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-398847DOI: 10.1038/s41598-019-48883-xISI: 000482709400017PubMedID: 31455808OAI: oai:DiVA.org:uu-398847DiVA, id: diva2:1380778
Funder
Swedish Research Council, 2016-06264Swedish Research Council, 2018-05498Knut and Alice Wallenberg Foundation, KAW 2017.0055Swedish Research Council, BR2013-5223The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), BR2013-5223The Wenner-Gren Foundation, UPD2017-0238The Wenner-Gren Foundation, UPD2018-0306
Note

Manuscript title: Direct involvement of RNA in mammalian prion protein aggregation: Involvement of RNA in rPrP aggregation

Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2019-12-19Bibliographically approved
In thesis
1. The role of RNA in prion aggregation and disease
Open this publication in new window or tab >>The role of RNA in prion aggregation and disease
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As humanity evolved to witness an exceptionally high standard of living, Alzheimer’s, cancer and diabetes gradually replaced infections as the main limiting factors in longevity. It is both disturbing and captivating that such degenerative conditions are caused by the most ubiquitous biomolecule – the protein. Indeed, proteins are not only the most functional, but also the least understood of the cellular biopolymers. It is then not surprising that many severe human ailments are associated with aberrant proteostasis. The key, causative mechanism of proteinopathy is protein aggregation. Naturally occurring and sometimes functional, aggregation is an auxiliary pathway in protein folding. In the context of a crowded cellular environment, folding and aggregation are the least and one of the least understood molecular processes, respectively. Unravelling one can help deconstruct the other and vice versa, but also can provide mechanistic insight on degenerative proteinopathies. A special class of proteins, which appear to propagate their own aggregation, occupy center-stage in the scientific field devoted to this goal. These proteins known as prions, can exist in at least two distinct forms. With the human prion, one of those is functional and benign and the other is infectious, aggregation prone, self-replicating and fatally pathogenic. As it happens, prion disease shares many of the descriptive features of other proteinaceous neuropathies. That, and the seductive idea that prions dwell in the twilight zone between folding and aggregation, have made the prion phenomenon a fixation for many molecular biologists. This thesis, although not the product of fixation, deals with one aspect of the prion process – the involvement of a molecular cofactor.

Of all plausible adjuvants, RNAs have been proposed as likely participants in the prion process. Their prominent secondary structures and attractive polyanionic surfaces allow RNAs to freely engage in interactions, at times transmitting conformational information through induced fit effects. The present work summarizes the influence of various RNAs on the aggregation profiles of three prionogenic model systems. The produced results indicate a generic role for RNA in the molecular processes prion propagation and aggregation. Altogether, this study illustrates a previously overlooked RNA function, of potential relevance for protein-based disease. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 81
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1620
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-338857 (URN)978-91-513-0208-9 (ISBN)
Public defence
2018-03-02, A1:107a, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2018-02-07 Created: 2018-01-14 Last updated: 2019-12-19

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