ArticleScientific reports2020
Mechanistic insights into the deleterious roles of Nasu-Hakola disease associated TREM2 variants.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 46 citations in OpenAlex.
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.Cell communication and signaling : CCS · 2026Review
- Cholecalciferol (vitamin D3) is an agonist of the Alzheimer's disease-associated immune receptor TREM2.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Review
- Synergistic reduction in interfacial flexibility of TREM2Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Article
- Biophysical characterization of TREM2 missense variants implicated in neurodegenerative disease.Computational and structural biotechnology journal · 2025Article
- Microglia in Health and Diseases: Integrative Hubs of the Central Nervous System (CNS).Cold Spring Harbor perspectives in biology · 2024Review
- Deciphering the Genetic Variation: A Comparative Analysis of Parental and Attenuated Strains of the QXL87 Vaccine for Infectious Bronchitis.Animals : an open access journal from MDPI · 2024Article
- Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.Acta neuropathologica · 2023Article
- Unveiling the Potentiality of Shikonin Derivatives Inhibiting SARS-CoV-2 Main Protease by Molecular Dynamic Simulation Studies.International journal of molecular sciences · 2023Article
- Molecular Docking and Dynamics Simulation of Natural Compounds from Betel Leaves (Molecules (Basel, Switzerland) · 2022Article
- Dynamic insights into the effects of nonsynonymous polymorphisms (nsSNPs) on loss of TREM2 function.Scientific reports · 2022Article
- Structural Consequence of Non-Synonymous Single-Nucleotide Variants in the N-Terminal Domain of LIS1.International journal of molecular sciences · 2022Article
- The emerging role of triggering receptor expressed on myeloid cell-2 in malignant tumor.Central-European journal of immunology · 2022Review
- Osteoporosis and Dementia: Establishing a Link.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2021Article
- Computational Insights into the Deleterious Impacts of Missense Variants onInternational journal of molecular sciences · 2021Article
- Article
- Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.International journal of molecular sciences · 2020Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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