Title : Neurodegenerative disease mutations in
TREM2 reveal a functional surface and distinct loss-of-function mechanisms
Abstract :
- Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases
- To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins
- Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer's disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function
- Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer's risk variants impact binding to a TREM2 ligand
- Additionally, the Alzheimer's risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family
- These findings provide a guide to structural and functional differences among genetic variants of TREM2 , indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders