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International Journal of Cell Biology
Volume 2013, Article ID 543803, 15 pages
Review Article

Synaptic Dysfunction in Prion Diseases: A Trafficking Problem?

Dulbecco Telethon Institute and Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri,” Via G. La Masa 19, 20156 Milano, Italy

Received 11 July 2013; Accepted 8 October 2013

Academic Editor: Alessio Cardinale

Copyright © 2013 Assunta Senatore et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Synaptic dysfunction is an important cause of neurological symptoms in prion diseases, a class of clinically heterogeneous neurodegenerative disorders caused by misfolding of the cellular prion protein ( ). Experimental data suggest that accumulation of misfolded in the endoplasmic reticulum (ER) may be crucial in synaptic failure, possibly because of the activation of the translational repression pathway of the unfolded protein response. Here, we report that this pathway is not operative in mouse models of genetic prion disease, consistent with our previous observation that ER stress is not involved. Building on our recent finding that ER retention of mutant impairs the secretory trafficking of calcium channels essential for synaptic function, we propose a model of pathogenicity in which intracellular retention of misfolded results in loss of function or gain of toxicity of -interacting proteins. This neurotoxic modality may also explain the phenotypic heterogeneity of prion diseases.