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The Journal of Neuroscience, December 3, 2008, 28(49):13258-13267; doi:10.1523/JNEUROSCI.3109-08.2008

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Neurobiology of Disease
Aggregated, Wild-Type Prion Protein Causes Neurological Dysfunction and Synaptic Abnormalities

Roberto Chiesa,¹ Pedro Piccardo,^2,3 Emiliano Biasini,^1,4 Bernardino Ghetti,² and David A. Harris⁴

¹Dulbecco Telethon Institute and Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20156, Milan, Italy, ²Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, ³Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852, and ⁴Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence should be addressed to either of the following: Roberto Chiesa, Dulbecco Telethon Institute and Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Via G. La Masa 19, 20156, Milan, Italy, Email: chiesa{at}marionegri.it; or David A. Harris, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, Email: dharris{at}wustl.edu

The neurotoxic forms of the prion protein (PrP) that cause neurodegeneration in prion diseases remain to be conclusively identified. Considerable evidence points to the importance of noninfectious oligomers of PrP in the pathogenic process. In this study, we describe lines of Tg(WT) transgenic mice that over-express wild-type PrP by either 5-fold or 10-fold (depending on whether the transgene array is, respectively, hemizygous or homozygous). Homozygous but not hemizygous Tg(WT) mice develop a spontaneous neurodegenerative illness characterized clinically by tremor and paresis. Both kinds of mice accumulate large numbers of punctate PrP deposits in the molecular layer of the cerebellum as well as in several other brain regions, and they display abnormally enlarged synaptic terminals accompanied by a dramatic proliferation of membranous structures. The over-expressed PrP in Tg(WT) mice assembles into an insoluble form that is mildly protease-resistant and is recognizable by aggregation-specific antibodies, but that is not infectious in transmission experiments. Together, our results demonstrate that noninfectious aggregates of wild-type PrP are neurotoxic, particularly to synapses, and they suggest common pathogenic mechanisms shared by prion diseases and nontransmissible neurodegenerative disorders associated with protein misfolding.

Key words: prion; transgenic; protein aggregation; synapse; wild-type; neurodegeneration

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Received July 4, 2008; revised Oct. 3, 2008; accepted Oct. 17, 2008.

Correspondence should be addressed to either of the following: Roberto Chiesa, Dulbecco Telethon Institute and Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Via G. La Masa 19, 20156, Milan, Italy, Email: chiesa{at}marionegri.it; or David A. Harris, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, Email: dharris{at}wustl.edu

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