Abstract
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.
Highlights
Prion diseases are invariably fatal, neurodegenerative disorders caused by misfolded and infectious conformers of the cellular prion protein (PrPC) termed prions
We further investigated how Sirpa expression levels varied during microglia development from embryonic day 17 (E17) to post-natal day 60 (P60) and after an immune challenge [35]
Prion diseases are characterized by the deposition of misfolded PrP in the brain associated to neuronal loss, vacuolation and astro- and microgliosis [1]
Summary
Prion diseases are invariably fatal, neurodegenerative disorders caused by misfolded and infectious conformers of the cellular prion protein (PrPC) termed prions. These diseases are characterized by extracellular deposition of partially protease-resistant PrP aggregates The role of SIRPα-mediated "don’t-eat-me" signaling in prion pathogenesis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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