Mechanistic insights into the deleterious roles of Nasu-Hakola disease associated TREM2 variants

Raju Dash,Ho Jin Choi,Il Soo Moon

doi:10.1038/s41598-020-60561-x

Abstract

Recently, the critical roles played by genetic variants of TREM2 (Triggering Receptor Expressed on Myeloid cells 2) in Alzheimer’s disease have been aggressively highlighted. However, few studies have focused on the deleterious roles of Nasu-Hakola disease (NHD) associated TREM2 variants. In order to get insights into the contributions made by these variants to neurodegeneration, we investigated the influences of four NHD associated TREM2 mutations (Y38C, W50C, T66M, and V126G) on loss-of-function, and followed this with in silico prediction and conventional molecular dynamics simulation. NHD mutations were predicted to be highly deleterious by eight different in silico bioinformatics tools and found to induce conformational changes by molecular dynamics simulation. As compared with the wild-type, the four variants produced substantial differences in the collective motions of loop regions, which not only promoted structural remodeling in the CDR2 (complementarity-determining region 2) loop but also in the CDR1 loop, by changing inter- and intra-loop hydrogen bonding networks. In addition, structural studies in a free energy landscape analysis showed that Y38, T66, and V126 are crucial for maintaining the structural features of CDR1 and CDR2 loops, and that mutations in these positions produced steric clashes and loss of ligand binding. These results showed the presence of mutations in the TREM2 ectodomain induced flexibility and caused structural alterations. Dynamical scenarios, as provided by the present study, may be critical to our understanding of the roles of these TREM2 mutations in neurodegenerative diseases.

Highlights

The critical roles played by genetic variants of TREM2 (Triggering Receptor Expressed on Myeloid cells 2) in Alzheimer’s disease have been aggressively highlighted
The precise mechanisms and molecular determinants of this neurodegenerative disease are incomplete, recent whole-genome sequencing studies have demonstrated altered genetic loci including those in TREM2 (Triggering Receptor Expressed on Myeloid cells 2) are associated with a markedly higher risk of progression to AD3,4
The present study provides in silico insights of the magnitudes of the damaging effects of TREM2 variants, of Nasu-Hakola disease (NHD) associated mutations, and provides classical molecular dynamics simulation-based descriptions of the structural dynamic behavior of TREM2 protein in the wild and mutated states

Summary

Introduction

The critical roles played by genetic variants of TREM2 (Triggering Receptor Expressed on Myeloid cells 2) in Alzheimer’s disease have been aggressively highlighted. At the molecular level, genetic variations in TREM2 have been linked with frontotemporal dementia (FTD) and Nasu-Hakola disease (NHD), the latter of which is characterized by demyelination, early-onset dementia, and bone cyst lipoma and known to be associated with Y38C, W50C, T66M, and V126G mutations in the ectodomains of TREM222–25. In this regard, Yeh et al showed that TREM2 variants, including AD-associated (R47H, R62H, and D87N) and NHD linked mutations (Y38C and T66M) reduce binding between TREM2 and its ligands. The present study provides in silico insights of the magnitudes of the damaging effects of TREM2 variants, of NHD associated mutations, and provides classical molecular dynamics simulation-based descriptions of the structural dynamic behavior of TREM2 protein in the wild and mutated states

Methods

Results

Conclusion