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GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different

Berta Puig1,2, Hermann C Altmeppen1, Luise Linsenmeier1

  • 1Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Plos Pathogens
|January 5, 2019
PubMed

Insights

Altering the GPI-anchor signal sequence of prion protein (PrPC) changes its localization and reduces disease progression in mice. This highlights the anchor

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • The cellular prion protein (PrPC) is crucial in prion diseases.
  • Its glycosylphosphatidylinositol (GPI)-anchor influences PrPC signaling and disease development.
  • The in vivo role of the GPI-anchor in PrPC localization, processing, and function is not well understood.

Purpose of the Study:

  • To investigate the in vivo role of the GPI-anchor signal sequence in PrPC localization, processing, and prion disease progression.
  • To determine if modifying the GPI-anchor signal sequence affects disease severity.

Main Methods:

  • Exchanged the PrPC GPI-anchor signal sequence with that of Thy-1 in cells and mice (PrPCGPIThy-1).
  • Analyzed GPI-anchor composition, subcellular localization, and proteolytic shedding.
  • Assessed prion disease progression, neuroinflammation (microglia/astrocyte activation), and MAPK signaling in PrPCGPIThy-1 mice after prion infection.

Main Results:

  • The modified GPI-anchor composition lacked sialic acid.
  • PrPCGPIThy-1 showed preferential axonal localization and reduced proteolytic shedding compared to PrPC.
  • PrPCGPIThy-1 mice exhibited delayed terminal disease, decreased neuroinflammation, and altered MAPK signaling post-prion infection.

Conclusions:

  • The GPI-anchor signal sequence fundamentally dictates GPI-anchor composition and protein subcellular localization.
  • Modifying the GPI-anchor influences PrPC processing and significantly impacts prion disease development in vivo.
  • Targeting the GPI-anchor offers a potential strategy for mitigating prion disease.

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