Evidence of trem2 variant associated with triple risk of Alzheimer's disease.
Evidence of trem2 variant associated with triple risk of Alzheimer's disease.
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DOI：
10.1371/journal.pone.0092648
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
El-Huneidi W
中科院分区：
文献类型：
--
作者：
Abduljaleel Z;Al-Allaf FA;Khan W;Athar M;Shahzad N;Taher MM;Elrobh M;Alanazi MS;El-Huneidi W
阿尔茨海默病是导致老年人痴呆的主要原因之一，会导致大脑不同区域的神经退化，导致记忆障碍和认知功能丧失。最近，一种罕见的变异被发现，它与阿尔茨海默病发病风险增加3倍有关。发现的罕见变异是TREM2外显子2环区的错义突变(rs75932628-T，Arg47His)。本研究的目的是通过分子动力学模拟研究TREM2基因变异(Arg47His)在结构和功能上的潜在意义。我们的结果表明，TREM2蛋白变异引起的改变对配体结合亲和力和结构构型都有显著影响。基于拯救条件下的分子动力学(MD)模拟，结果证实了该变异体(Arg47His)的天然形式可能与其致密性改善有关，从而改善了蛋白质折叠。在不同温度下进行蛋白质模拟。300K时，TREM2蛋白理论模型的偏差由10 ns时的2.0ó增大。相反，Arg47His突变的偏差在模拟结束前(t = 10 ns)保持在1.2？，这表明Arg47His已经达到折叠状态。突变残基是一个高度保守的区域，类似于“免疫球蛋白V-SET”和“免疫球蛋白样折叠”。综上所述，这项研究的结果提供了一个生物物理学的洞察力，即所研究的变体如何有助于阿尔茨海默病的遗传易感性。
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.
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DOI：
10.1096/fj.08-127530
发表时间：
2009-09
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Bromberg Y;Overton J;Vaisse C;Leibel RL;Rost B
通讯作者：
Rost B
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
14.9
作者：
Bromberg Y;Rost B
通讯作者：
Rost B
DOI：
10.1016/j.bbapap.2010.06.014
发表时间：
2010-09-01
影响因子：
3.2
作者：
Kamal, Md. Zahid;Ahmad, Shoeb;Rao, Nalam Madhusudhana
通讯作者：
Rao, Nalam Madhusudhana
影响因子：
13.6
作者：
Xu, Xiaojuan;Xiao, Jijun;Xiao, Heming
通讯作者：
Xiao, Heming