PHAGO Publications
An Alzheimer associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function
K. Schlepckow, G. Kleinberger, A. Fukumori, R. Feederle, S.F. Lichtenthaler, H. Steiner & C. Haass
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.