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Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease
Alzheimer’s disease is one of the main causes of dementia among elderly individuals and leads to the neurodegeneration of different areas of the brain, resulting in memory impairments and loss of cognitive functions. Recently, a rare variant that is associated with 3-fold higher risk of Alzheimer’s...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963925/ https://www.ncbi.nlm.nih.gov/pubmed/24663666 http://dx.doi.org/10.1371/journal.pone.0092648 |
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author | Abduljaleel, Zainularifeen Al-Allaf, Faisal A. Khan, Wajahatullah Athar, Mohammad Shahzad, Naiyer Taher, Mohiuddin M. Elrobh, Mohamed Alanazi, Mohammed S. El-Huneidi, Waseem |
author_facet | Abduljaleel, Zainularifeen Al-Allaf, Faisal A. Khan, Wajahatullah Athar, Mohammad Shahzad, Naiyer Taher, Mohiuddin M. Elrobh, Mohamed Alanazi, Mohammed S. El-Huneidi, Waseem |
author_sort | Abduljaleel, Zainularifeen |
collection | PubMed |
description | Alzheimer’s disease is one of the main causes of dementia among elderly individuals and leads to the neurodegeneration of different areas of the brain, resulting in memory impairments and loss of cognitive functions. Recently, a rare variant that is associated with 3-fold higher risk of Alzheimer’s disease onset has been found. The rare variant discovered is a missense mutation in the loop region of exon 2 of Trem2 (rs75932628-T, Arg47His). The aim of this study was to investigate the evidence for potential structural and functional significance of Trem2 gene variant (Arg47His) through molecular dynamics simulations. Our results showed the alteration caused due to the variant in TREM2 protein has significant effect on the ligand binding affinity as well as structural configuration. Based on molecular dynamics (MD) simulation under salvation, the results confirmed that native form of the variant (Arg47His) might be responsible for improved compactness, hence thereby improved protein folding. Protein simulation was carried out at different temperatures. At 300K, the deviation of the theoretical model of TREM2 protein increased from 2.0 Å at 10 ns. In contrast, the deviation of the Arg47His mutation was maintained at 1.2 Å until the end of the simulation (t = 10 ns), which indicated that Arg47His had reached its folded state. The mutant residue was a highly conserved region and was similar to “immunoglobulin V-set” and “immunoglobulin-like folds”. Taken together, the result from this study provides a biophysical insight on how the studied variant could contribute to the genetic susceptibility to Alzheimer’s disease. |
format | Online Article Text |
id | pubmed-3963925 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39639252014-03-27 Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease Abduljaleel, Zainularifeen Al-Allaf, Faisal A. Khan, Wajahatullah Athar, Mohammad Shahzad, Naiyer Taher, Mohiuddin M. Elrobh, Mohamed Alanazi, Mohammed S. El-Huneidi, Waseem PLoS One Research Article Alzheimer’s disease is one of the main causes of dementia among elderly individuals and leads to the neurodegeneration of different areas of the brain, resulting in memory impairments and loss of cognitive functions. Recently, a rare variant that is associated with 3-fold higher risk of Alzheimer’s disease onset has been found. The rare variant discovered is a missense mutation in the loop region of exon 2 of Trem2 (rs75932628-T, Arg47His). The aim of this study was to investigate the evidence for potential structural and functional significance of Trem2 gene variant (Arg47His) through molecular dynamics simulations. Our results showed the alteration caused due to the variant in TREM2 protein has significant effect on the ligand binding affinity as well as structural configuration. Based on molecular dynamics (MD) simulation under salvation, the results confirmed that native form of the variant (Arg47His) might be responsible for improved compactness, hence thereby improved protein folding. Protein simulation was carried out at different temperatures. At 300K, the deviation of the theoretical model of TREM2 protein increased from 2.0 Å at 10 ns. In contrast, the deviation of the Arg47His mutation was maintained at 1.2 Å until the end of the simulation (t = 10 ns), which indicated that Arg47His had reached its folded state. The mutant residue was a highly conserved region and was similar to “immunoglobulin V-set” and “immunoglobulin-like folds”. Taken together, the result from this study provides a biophysical insight on how the studied variant could contribute to the genetic susceptibility to Alzheimer’s disease. Public Library of Science 2014-03-24 /pmc/articles/PMC3963925/ /pubmed/24663666 http://dx.doi.org/10.1371/journal.pone.0092648 Text en © 2014 Abduljaleel et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Abduljaleel, Zainularifeen Al-Allaf, Faisal A. Khan, Wajahatullah Athar, Mohammad Shahzad, Naiyer Taher, Mohiuddin M. Elrobh, Mohamed Alanazi, Mohammed S. El-Huneidi, Waseem Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease |
title | Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease |
title_full | Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease |
title_fullStr | Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease |
title_full_unstemmed | Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease |
title_short | Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease |
title_sort | evidence of trem2 variant associated with triple risk of alzheimer’s disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963925/ https://www.ncbi.nlm.nih.gov/pubmed/24663666 http://dx.doi.org/10.1371/journal.pone.0092648 |
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