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

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-offunction, 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. The accumulation of amyloid-β (Aβ) in brain parenchyma is the main hallmark of Alzheimer's disease (AD), which results in a slow progressive decline of cognitive function by causing the formation of intracellular neurofibrillary tangles, synapse loss, and cell death 1,2. Although 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 AD 3,4. TREM2 is a V-type immunoglobulin (Ig) domain-containing transmembrane protein that is expressed in osteoclasts, microglia, alveolar macrophages, and other mononuclear phagocytes 4. The activation of TREM2 is initiated by anionic lipids, such as bacterial lipopolysaccharide (LPS) and phospholipids, and several putative ligands like apolipoprotein J (ApoJ) and apolipoprotein E (ApoE) have been reported to bind to TREM2 5-7. Upon ligand binding, TREM2 recruits protein tyrosine kinase SYK through an adapter protein known as DNAX-activating protein of 12 kDa (DAP12), which interacts with the transmembrane region of TREM2 8-10. This binding is followed by a cascade of signaling events, which include the activations of MAPK and PI3K, and regulates the phagocytosis of cellular debris and the inflammatory responses of ...

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