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M511174200v1
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Papers In Press, published online ahead of print March 22, 2006
J. Biol. Chem, 10.1074/jbc.M511174200
Submitted on October 13, 2005
Accepted on March 22, 2006

Amyloid fibrils of mammalian prion protein are highly toxic to cultured cells and primary neurons

Vera Novitskaya, Olga V. Bocharova, Igor Bronstein, and Ilia V. Baskakov

Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201

Corresponding Author: baskakov{at}umbi.umd.edu

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 to that exhibited by soluble small beta -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 beta -oligomers was substantially reduced, when expression of endogenous PrPC was down-regulated by siRNA. In opposition to the beta -oligomer and amyloid fibrils of rPrP, the monomeric {alfa}-helical form of rPrP stimulated neurite outgrowth and survival of neurons. These studies illustrated that both soluble beta -oligomer and amyloid fibrils of the prion protein are intrinsically toxic, and confirmed that endogenously expressed PrPC is required for mediating the toxicity of abnormally folded external PrP aggregates.


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