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Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling
Prion diseases are neurodegenerative conditions caused by misfolding of the prion protein, leading to conspicuous neuronal loss and intense microgliosis. Recent experimental evidence point towards a protective role of microglia against prion-induced neurodegeneration, possibly through elimination of...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435345/ https://www.ncbi.nlm.nih.gov/pubmed/28545141 http://dx.doi.org/10.1371/journal.pone.0177876 |
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author | Nuvolone, Mario Paolucci, Marta Sorce, Silvia Kana, Veronika Moos, Rita Matozaki, Takashi Aguzzi, Adriano |
author_facet | Nuvolone, Mario Paolucci, Marta Sorce, Silvia Kana, Veronika Moos, Rita Matozaki, Takashi Aguzzi, Adriano |
author_sort | Nuvolone, Mario |
collection | PubMed |
description | Prion diseases are neurodegenerative conditions caused by misfolding of the prion protein, leading to conspicuous neuronal loss and intense microgliosis. Recent experimental evidence point towards a protective role of microglia against prion-induced neurodegeneration, possibly through elimination of prion-containing apoptotic bodies. The molecular mechanisms by which microglia recognize and eliminate apoptotic cells in the context of prion diseases are poorly defined. Here we investigated the possible involvement of signal regulatory protein α (SIRPα), a key modulator of host cell phagocytosis; SIRPα is encoded by the Sirpa gene that is genetically linked to the prion gene Prnp. We found that Sirpa transcripts are highly enriched in microglia cells within the brain. However, Sirpa mRNA levels were essentially unaltered during the course of experimental prion disease despite upregulation of other microglia-enriched transcripts. To study the involvement of SIRPα in prion pathogenesis in vivo, mice expressing a truncated SIRPα protein unable to inhibit phagocytosis were inoculated with rodent-adapted scrapie prions of the 22L strain. Homozygous and heterozygous Sirpa mutants and wild-type mice experienced similar incubation times after inoculation with either of two doses of 22L prions. Moreover, the extent of neuronal loss, microgliosis and abnormal prion protein accumulation was not significantly affected by Sirpa genotypes. Collectively, these data indicate that SIRPα-mediated phagocytosis is not a major determinant in prion disease pathogenesis. It will be important to search for additional candidates mediating prion phagocytosis, as this mechanism may represent an important target of antiprion therapies. |
format | Online Article Text |
id | pubmed-5435345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54353452017-05-26 Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling Nuvolone, Mario Paolucci, Marta Sorce, Silvia Kana, Veronika Moos, Rita Matozaki, Takashi Aguzzi, Adriano PLoS One Research Article Prion diseases are neurodegenerative conditions caused by misfolding of the prion protein, leading to conspicuous neuronal loss and intense microgliosis. Recent experimental evidence point towards a protective role of microglia against prion-induced neurodegeneration, possibly through elimination of prion-containing apoptotic bodies. The molecular mechanisms by which microglia recognize and eliminate apoptotic cells in the context of prion diseases are poorly defined. Here we investigated the possible involvement of signal regulatory protein α (SIRPα), a key modulator of host cell phagocytosis; SIRPα is encoded by the Sirpa gene that is genetically linked to the prion gene Prnp. We found that Sirpa transcripts are highly enriched in microglia cells within the brain. However, Sirpa mRNA levels were essentially unaltered during the course of experimental prion disease despite upregulation of other microglia-enriched transcripts. To study the involvement of SIRPα in prion pathogenesis in vivo, mice expressing a truncated SIRPα protein unable to inhibit phagocytosis were inoculated with rodent-adapted scrapie prions of the 22L strain. Homozygous and heterozygous Sirpa mutants and wild-type mice experienced similar incubation times after inoculation with either of two doses of 22L prions. Moreover, the extent of neuronal loss, microgliosis and abnormal prion protein accumulation was not significantly affected by Sirpa genotypes. Collectively, these data indicate that SIRPα-mediated phagocytosis is not a major determinant in prion disease pathogenesis. It will be important to search for additional candidates mediating prion phagocytosis, as this mechanism may represent an important target of antiprion therapies. Public Library of Science 2017-05-17 /pmc/articles/PMC5435345/ /pubmed/28545141 http://dx.doi.org/10.1371/journal.pone.0177876 Text en © 2017 Nuvolone et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Nuvolone, Mario Paolucci, Marta Sorce, Silvia Kana, Veronika Moos, Rita Matozaki, Takashi Aguzzi, Adriano Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling |
title | Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling |
title_full | Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling |
title_fullStr | Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling |
title_full_unstemmed | Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling |
title_short | Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling |
title_sort | prion pathogenesis is unaltered in the absence of sirpα-mediated "don't-eat-me" signaling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435345/ https://www.ncbi.nlm.nih.gov/pubmed/28545141 http://dx.doi.org/10.1371/journal.pone.0177876 |
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