Prion pathogenesis is unaltered in the absence of SIRPalpha-mediated "don't-eat-me" signaling

M. Nuvolone, M. Paolucci, S. Sorce, V. Kana, R. Moos, T. Matozaki, A. Aguzzi

Research output: Contribution to journalArticlepeer-review


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 alpha (SIRPalpha), a key modulator of host cell phagocytosis; SIRPalpha 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 SIRPalpha in prion pathogenesis in vivo, mice expressing a truncated SIRPalpha 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 SIRPalpha-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.
Original languageEnglish
Pages (from-to)e0177876
JournalPLoS One
Issue number5
Publication statusPublished - May 17 2017
Externally publishedYes


  • Animals
  • Disease Progression
  • Gene Expression Regulation
  • Mice
  • Microglia/metabolism/pathology
  • Mutation
  • Phagocytosis
  • Prion Diseases/genetics/metabolism/pathology
  • Prion Proteins/metabolism
  • Receptors, Immunologic/genetics/metabolism


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