PHAGO Publications

30/08/2017

An Alzheimer associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function

EMBO Molecular Medicine - K. Schlepckow, G. Kleinberger, A. Fukumori, R. Feederle, S.F. Lichtenthaler, H. Steiner & C. Haass

K. Schlepckow, G. Kleinberger, A. Fukumori, R. Feederle, S.F. Lichtenthaler, H. Steiner & C. Haass

DOI 10.15252/emmm.201707672

 

Synopsis

 

Sequence variation in the microglial receptor protein TREM2 is linked to risk for Alzheimer’s disease; availability of full-length TREM2 at the cell surface determines phagocytic activity. Different mutations affect localization and processing of TREM2 differently but resulting in a similar phenotype

  • the sheddase site between positions 157&158 was identified using immunoprecipitation and mass spectrometry
  • ADAM10 has been confirmed as main sheddase and ADAM17 implicated in shedding at the same site after PKC activation
  • the H157Y variant displays reduced full length TREM2 on the cell surface and thereby a similar phenotype to known mutations in the Ig-like domain that show reduced cell surface localization due to ER retention of misfolded TREM2 protein
  • phagocytic activity in cells expressing the H157Y variant is likewise reduced
  • the c-terminal fragment remaining in the membrane after shedding is also reduced by enhanced degradation. It can be stabilized by binding to DAP12.
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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies.

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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies.