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
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.