HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 19, 13828-13836, May 12, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/19/13828    most recent M511174200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Novitskaya, V. Articles by Baskakov, I. V. Search for Related Content PubMed PubMed Citation Articles by Novitskaya, V. Articles by Baskakov, I. V. Social Bookmarking                      What's this?

Amyloid Fibrils of Mammalian Prion Protein Are Highly Toxic to Cultured Cells and Primary Neurons^*

Vera Novitskaya¹, Olga V. Bocharova², Igor Bronstein³, and Ilia V. Baskakov^¶4

From the Medical Biotechnology Center, University of Maryland Biotechnology Institute, and ^¶Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201 and National Institute for Medical Research, Physical Biochemistry Division, The Ridgeway, Mill Hill, London, NW7 1AA, United Kingdom

A growing body of evidence indicates that small, soluble oligomeric species generated from a variety of proteins and peptides rather than mature amyloid fibrils are inherently highly cytotoxic. Here, we show for the first time that mature amyloid fibrils produced from full-length recombinant mammalian prion protein (rPrP) were highly toxic to cultured cells and primary hippocampal and cerebella neurons. Fibrils induced apoptotic cell death in a time- and dose-dependent manner. The toxic effect of fibrils was comparable with that exhibited by soluble small -oligomers generated from the same protein. Fibrils prepared from insulin were not toxic, suggesting that the toxic effect was not solely due to the highly polymeric nature of the fibrillar form. The cell death caused by rPrP fibrils or -oligomers was substantially reduced when expression of endogenous PrP^C was down-regulated by small interfering RNAs. In opposition to the -oligomer and amyloid fibrils of rPrP, the monomeric -helical form of rPrP stimulated neurite out-growth and survival of neurons. These studies illustrated that both soluble -oligomer and amyloid fibrils of the prion protein are intrinsically toxic and confirmed that endogenously expressed PrP^C is required for mediating the toxicity of abnormally folded external PrP aggregates.

Received for publication, October 13, 2005 , and in revised form, February 21, 2006.

^* This work was supported in part National Institutes of Health Grants NS046291 and NS045585 (to I. V. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

² Present address: Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia, 117997.

³ Supported by the Department of Health, UK.

⁴ To whom correspondence should be addressed: Medical Biotechnology Center, University of Maryland Biotechnology Institute, 725 W. Lombard St., Baltimore, MD 21201. Tel.: 410-706-4562; Fax: 410-706-8184; E-mail: Baskakov{at}umbi.umd.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. P. B. Gomes, T. A. Millen, P. S. Ferreira, N. L. C. e Silva, T. C. R. G. Vieira, M. S. Almeida, J. L. Silva, and Y. Cordeiro Prion Protein Complexed to N2a Cellular RNAs through Its N-terminal Domain Forms Aggregates and Is Toxic to Murine Neuroblastoma Cells J. Biol. Chem., July 11, 2008; 283(28): 19616 - 19625. [Abstract] [Full Text] [PDF]

				S. Rigacci, M. Bucciantini, A. Relini, A. Pesce, A. Gliozzi, A. Berti, and M. Stefani The (1-63) Region of the p53 Transactivation Domain Aggregates In Vitro into Cytotoxic Amyloid Assemblies Biophys. J., May 1, 2008; 94(9): 3635 - 3646. [Abstract] [Full Text] [PDF]

				M. F. M. Engel, L. Khemtemourian, C. C. Kleijer, H. J. D. Meeldijk, J. Jacobs, A. J. Verkleij, B. de Kruijff, J. A. Killian, and J. W. M. Hoppener Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane PNAS, April 22, 2008; 105(16): 6033 - 6038. [Abstract] [Full Text] [PDF]

				R. Gerber, A. Tahiri-Alaoui, P.J. Hore, and W. James Conformational pH dependence of intermediate states during oligomerization of the human prion protein Protein Sci., March 1, 2008; 17(3): 537 - 544. [Abstract] [Full Text] [PDF]

				Z. Berger, H. Roder, A. Hanna, A. Carlson, V. Rangachari, M. Yue, Z. Wszolek, K. Ashe, J. Knight, D. Dickson, et al. Accumulation of Pathological Tau Species and Memory Loss in a Conditional Model of Tauopathy J. Neurosci., April 4, 2007; 27(14): 3650 - 3662. [Abstract] [Full Text] [PDF]

				R. Gerber, A. Tahiri-Alaoui, P. J. Hore, and W. James Oligomerization of the Human Prion Protein Proceeds via a Molten Globule Intermediate J. Biol. Chem., March 2, 2007; 282(9): 6300 - 6307. [Abstract] [Full Text] [PDF]

				L. Fioriti, N. Angeretti, L. Colombo, A. De Luigi, A. Colombo, C. Manzoni, M. Morbin, F. Tagliavini, M. Salmona, R. Chiesa, et al. Neurotoxic and Gliotrophic Activity of a Synthetic Peptide Homologous to Gerstmann-Straussler-Scheinker Disease Amyloid Protein J. Neurosci., February 14, 2007; 27(7): 1576 - 1583. [Abstract] [Full Text] [PDF]

				C. Canale, S. Torrassa, P. Rispoli, A. Relini, R. Rolandi, M. Bucciantini, M. Stefani, and A. Gliozzi Natively Folded HypF-N and Its Early Amyloid Aggregates Interact with Phospholipid Monolayers and Destabilize Supported Phospholipid Bilayers Biophys. J., December 15, 2006; 91(12): 4575 - 4588. [Abstract] [Full Text] [PDF]