Sanghera, Narinder, Wall, M. (Mark), Venien-Bryan, Catherine and Pinheiro, Teresa J. T.. (2008) Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology. Biochimica et Biophysica Acta - Proteins and Proteomics, Vol.1784 (No.6). pp. 873-881. ISSN 1570-9639

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Abstract

Prion diseases are characterised at autopsy by neuronal loss and accumulation of amorphous protein aggregates and/or amyloid fibrils in the brains of humans and animals. These protein deposits result from the conversion of the cellular, mainly a-helical prion protein (PrPC) to the beta-sheet-rich isoform (PrPSc). Although the pathogenic mechanism of prion diseases is not fully understood, it appears that protein aggregation is itself neurotoxic and not the product of cell death. The precise nature of the neurotoxic species and mechanism of cell death are yet to be determined, although recent studies with other amyloidogenic proteins suggest that ordered pre-fibFillar or oligomeric forms may be responsible for cellular dysfunction. In this study we have refolded recombinant prion protein (rPrP) to two distinct forms rich in beta-sheet structure with an intact disulphide bond. Here we report on the structural properties of globular aggregates and pre-fibrils of rPrP and show that both states are toxic to neuronal cells in culture. We show that exogenous rPrP aggregates are internalised by neuronal cells and found in the cytoplasm. We also measured the changes in electrophysiological properties of cultured neuronal cells on exposure to exogenous prion aggregates and discuss the implications of these findings. (C) 2008 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QR Microbiology
Divisions:	Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Prions, Prion diseases, Amyloid beta-protein, Aggregation (Chemistry), Electrophysiology, Globular proteins
Journal or Publication Title:	Biochimica et Biophysica Acta - Proteins and Proteomics
Publisher:	Elsevier BV
ISSN:	1570-9639
Date:	June 2008
Volume:	Vol.1784
Number:	No.6
Number of Pages:	9
Page Range:	pp. 873-881
Identification Number:	10.1016/j.bbapap.2008.02.017
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC)
Grant number:	88/BS516471 (BBSRC), IIP0206/008 (BBSRC)
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URI:	http://wrap.warwick.ac.uk/id/eprint/29932

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