Globular and pre-fibrillar prion aggregates are toxic to neuronal cells and perturb their electrophysiology
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 1570-9639Full text not available from this repository.
Official URL: http://dx.doi.org/10.1016/j.bbapap.2008.02.017
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|
|Official Date:||June 2008|
|Number of Pages:||9|
|Page Range:||pp. 873-881|
|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)|
 C.M. Dobson, Protein folding and misfolding, Nature 426 (2003) 884–890.
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