Synaptic Dysfunction in Prion Diseases: A Trafficking Problem?
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 (PrPC). Experimental data suggest that accumulation of misfolded PrPC in the endoplasmic reticulum...
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| Format: | Article |
| Language: | English |
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Wiley
2013-01-01
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| Series: | International Journal of Cell Biology |
| Online Access: | http://dx.doi.org/10.1155/2013/543803 |
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| author | Assunta Senatore Elena Restelli Roberto Chiesa |
| author_facet | Assunta Senatore Elena Restelli Roberto Chiesa |
| author_sort | Assunta Senatore |
| collection | DOAJ |
| description | 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 (PrPC). Experimental data suggest that accumulation of misfolded PrPC 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 PrPC impairs the secretory trafficking of calcium channels essential for synaptic function, we propose a model of pathogenicity in which intracellular retention of misfolded PrPC results in loss of function or gain of toxicity of PrPC-interacting proteins. This neurotoxic modality may also explain the phenotypic heterogeneity of prion diseases. |
| format | Article |
| id | doaj-art-a7aecc9c736d4601bca95f5c16c5bce5 |
| institution | OA Journals |
| issn | 1687-8876 1687-8884 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Cell Biology |
| spelling | doaj-art-a7aecc9c736d4601bca95f5c16c5bce52025-08-20T02:20:57ZengWileyInternational Journal of Cell Biology1687-88761687-88842013-01-01201310.1155/2013/543803543803Synaptic Dysfunction in Prion Diseases: A Trafficking Problem?Assunta Senatore0Elena Restelli1Roberto Chiesa2Dulbecco Telethon Institute and Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri,” Via G. La Masa 19, 20156 Milano, ItalyDulbecco Telethon Institute and Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri,” Via G. La Masa 19, 20156 Milano, ItalyDulbecco Telethon Institute and Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri,” Via G. La Masa 19, 20156 Milano, ItalySynaptic 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 (PrPC). Experimental data suggest that accumulation of misfolded PrPC 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 PrPC impairs the secretory trafficking of calcium channels essential for synaptic function, we propose a model of pathogenicity in which intracellular retention of misfolded PrPC results in loss of function or gain of toxicity of PrPC-interacting proteins. This neurotoxic modality may also explain the phenotypic heterogeneity of prion diseases.http://dx.doi.org/10.1155/2013/543803 |
| spellingShingle | Assunta Senatore Elena Restelli Roberto Chiesa Synaptic Dysfunction in Prion Diseases: A Trafficking Problem? International Journal of Cell Biology |
| title | Synaptic Dysfunction in Prion Diseases: A Trafficking Problem? |
| title_full | Synaptic Dysfunction in Prion Diseases: A Trafficking Problem? |
| title_fullStr | Synaptic Dysfunction in Prion Diseases: A Trafficking Problem? |
| title_full_unstemmed | Synaptic Dysfunction in Prion Diseases: A Trafficking Problem? |
| title_short | Synaptic Dysfunction in Prion Diseases: A Trafficking Problem? |
| title_sort | synaptic dysfunction in prion diseases a trafficking problem |
| url | http://dx.doi.org/10.1155/2013/543803 |
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