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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

与早发性阿尔茨海默病相关的病原性的PSEN1 Ala285Val突变的鉴定

卷 17, 期 5, 2020

页: [438 - 445] 页: 8

弟呕挨: 10.2174/1567205017666200626210727

价格: $65

摘要

背景:早老素1（PSEN1）被认为是早发性阿尔茨海默病(AD)最常见的致病基因。 方法:研究对象为40多岁时出现渐进性记忆减退的患者。诊断中常应用大量的神经心理测试和神经影像。使用全外显子组测序对患者进行遗传学检测以评估可能的突变。经由电脑模拟预测程序对错义突变的致病性质及其三维蛋白质结构进行预测。 结果:1例韩国早发性阿尔茨海默病（EOAD）患者出现PSEN1 (NM_000021.3: c.1027T>C p.Ala285Val)致病性突变。磁共振扫描显示轻度左颞叶萎缩。双侧颞顶叶氟（18F）脱氧葡糖正电子发射x线断层摄影(FDG-PET)扫描显示低代谢，双侧额叶、顶叶、颞叶18F-Florbetaben-PET (FBB-PET)显示淀粉样蛋白沉积增多，推测为临床前AD。蛋白质模拟结果表明，p.Ala285Val位于随机线圈区域，可能在该区域产生额外的应力，导致丙氨酸残基被缬氨酸取代。之前的体外研究证实了这一预测，即与野生型对照组相比，p.Trp165Cys导致COS-1和HEK293细胞系的细胞中，Aβ42/Aβ40比值升高。 结论: 综上，PSEN1的临床特点及突变的影响有助于我们了解PSEN1在AD发病机制中的作用，有助于该病的诊断和治疗。需要进一步的体内研究来评估PSEN1 p.Ala285Val突变在AD进展中的作用。

关键词: 阿尔茨海默病(AD)，早老素1（PSEN1），p.Ala285Val，遗传学，突变，神经退行性基因。

« Previous Next »
[1]
Giau VV, Bagyinszky E, Yang YS, Youn YC, An SSA, Kim SY. Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. Sci Rep 2019; 9(1): 8368.
[http://dx.doi.org/10.1038/s41598-019-44848-2] [PMID: 31182772]
[2]
Giau VV, Senanarong V, Bagyinszky E, An SSA, Kim S. Analysis of 50 neurodegenerative genes in clinically diagnosed early-onset Alzheimer’s disease. Int J Mol Sci 2019; 20(6) E1514
[http://dx.doi.org/10.3390/ijms20061514] [PMID: 30917570]
[3]
Giau VV, Bagyinszky E, Youn YC, An SSA, Kim S. APP, PSEN1, and PSEN2 mutations in asian patients with early-onset Alzheimer disease. Int J Mol Sci 2019; 20(19) E4757
[http://dx.doi.org/10.3390/ijms20194757] [PMID: 31557888]
[4]
Giau VV, Lee H, Shim KH, Bagyinszky E, An SSA. Genome-editing applications of CRISPR-Cas9 to promote in vitro studies of Alzheimer’s disease. Clin Interv Aging 2018; 13: 221-33.
[http://dx.doi.org/10.2147/CIA.S155145] [PMID: 29445268]
[5]
Van der Flier WM. Clinical heterogeneity in familial Alzheimer’s disease. Lancet Neurol 2016; 15(13): 1296-8.
[http://dx.doi.org/10.1016/S1474-4422(16)30275-7] [PMID: 27777021]
[6]
Ryman DC, Acosta-Baena N, Aisen PS, et al. Dominantly inherited Alzheimer network. Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis. Neurology 2014; 83(3): 253-60.
[http://dx.doi.org/10.1212/WNL.0000000000000596] [PMID: 24928124]
[7]
Giau VV, Wang MJ, Bagyinszky E, Youn YC, An SSA, Kim S. Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer’s disease with parkinsonism. Neurobiol Aging 2018; 72: 188.e13-7.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.003] [PMID: 30180983]
[8]
Senanarong V, An SSA, Vo Van G, Limwongse C, Bagyinszky E, Kim S. Pathogenic PSEN1 Glu184Gly mutation in a family from Thailand with probable autosomal dominant early onset Alzheimer’s disease. Diagnostics (Basel) 2020; 10(3): 135.
[9]
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci USA 2017; 114(4): E476-85.
[http://dx.doi.org/10.1073/pnas.1618657114] [PMID: 27930341]
[10]
Borchelt DR, Thinakaran G, Eckman CB, et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 1996; 17(5): 1005-13.
[http://dx.doi.org/10.1016/S0896-6273(00)80230-5] [PMID: 8938131]
[11]
Murayama O, Tomita T, Nihonmatsu N, et al. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci Lett 1999; 265(1): 61-3.
[http://dx.doi.org/10.1016/S0304-3940(99)00187-1] [PMID: 10327206]
[12]
Xia D, Watanabe H, Wu B, et al. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer’s disease. Neuron 2015; 85(5): 967-81.
[http://dx.doi.org/10.1016/j.neuron.2015.02.010] [PMID: 25741723]
[13]
Giau VV, Bagyinszky E, An SSA, Kim S. Clinical genetic strategies for early onset neurodegenerative diseases. Mol Cell Toxicol 2018; 14(2): 123-42.
[http://dx.doi.org/10.1007/s13273-018-0015-3]
[14]
Ikeda M, Sharma V, Sumi SM, et al. The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients. Ann Neurol 1996; 40(6): 912-7.
[http://dx.doi.org/10.1002/ana.410400614] [PMID: 9007097]
[15]
Aoki M, Abe K, Oda N, et al. A presenilin-1 mutation in a Japanese family with Alzheimer’s disease and distinctive abnormalities on cranial MRI. Neurology 1997; 48(4): 1118-20.
[http://dx.doi.org/10.1212/WNL.48.4.1118] [PMID: 9109915]
[16]
Page RM, Baumann K, Tomioka M, et al. Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem 2008; 283(2): 677-83.
[http://dx.doi.org/10.1074/jbc.M708754200] [PMID: 17962197]
[17]
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease Report of the NINCDS‐ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34(7): 939-9.
[18]
Van Giau V, An SSA, Bagyinszky E, Kim S. Gene panels and primers for next generation sequencing studies on neurodegenerative disorders. Mol Cell Toxicol 2015; 11(2): 89-143.
[http://dx.doi.org/10.1007/s13273-015-0011-9]
[19]
Källberg M, Wang H, Wang S, et al. Template-based protein structure modeling using the RaptorX web server. Nat Protoc 2012; 7(8): 1511-22.
[http://dx.doi.org/10.1038/nprot.2012.085] [PMID: 22814390]
[20]
Ch’ng GS, An SS, Bae SO, Bagyinszky E, Kim S. Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family. Neuropsychiatr Dis Treat 2015; 11: 2315-22.
[PMID: 26396515]
[21]
Hamaguchi T, Morinaga A, Tsukie T, Kuwano R, Yamada M. A novel presenilin 1 mutation (L282F) in familial Alzheimer’s disease. J Neurol 2009; 256(9): 1575-7.
[http://dx.doi.org/10.1007/s00415-009-5154-y] [PMID: 19430857]
[22]
Aldudo J, Bullido MJ, Arbizu T, Oliva R, Valdivieso F. Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer’s disease. Neurosci Lett 1998; 240(3): 174-6.
[http://dx.doi.org/10.1016/S0304-3940(97)00950-6] [PMID: 9502232]
[23]
Ryan NS, Nicholas JM, Weston PSJ, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: A case series. Lancet Neurol 2016; 15(13): 1326-35.
[http://dx.doi.org/10.1016/S1474-4422(16)30193-4] [PMID: 27777022]
[24]
Clark RF, Hutton M, Fuldner M, et al. Alzheimer’s Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 1995; 11(2): 219-22.
[http://dx.doi.org/10.1038/ng1095-219] [PMID: 7550356]
[25]
Dermaut B, Kumar-Singh S, De Jonghe C, et al. Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer’s disease due to a novel presenilin 1 mutation. Brain 2001; 124(Pt 12): 2383-92.
[http://dx.doi.org/10.1093/brain/124.12.2383] [PMID: 11701593]
[26]
Hiltunen M, Helisalmi S, Mannermaa A, et al. Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer’s disease family: An Alu core sequence-stimulated recombination? Eur J Hum Genet 2000; 8(4): 259-66.
[http://dx.doi.org/10.1038/sj.ejhg.5200423] [PMID: 10854108]
[27]
Le Guennec K, Veugelen S, Quenez O, et al. Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds. Neurobiol Dis 2017; 104: 97-103.
[http://dx.doi.org/10.1016/j.nbd.2017.04.020] [PMID: 28461250]
[28]
Lam B, Khan A, Keith J, et al. Characterizing familial corticobasal syndrome due to Alzheimer’s disease pathology and PSEN1 mutations. Alzheimers Dement 2017; 13(5): 520-30.
[http://dx.doi.org/10.1016/j.jalz.2016.08.014] [PMID: 27743520]
[29]
Sánchez-Valle R, Lladó A, Ezquerra M, Rey MJ, Rami L, Molinuevo JL. A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas. Eur J Neurol 2007; 14(12): 1409-12.
[http://dx.doi.org/10.1111/j.1468-1331.2007.01988.x] [PMID: 18028191]
[30]
Tabira T, Chui DH, Nakayama H, Kuroda S, Shibuya M. Alzheimer’s disease with spastic paresis and cotton wool type plaques. J Neurosci Res 2002; 70(3): 367-72.
[http://dx.doi.org/10.1002/jnr.10392] [PMID: 12391599]
[31]
Marrosu MG, Floris G, Costa G, et al. Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation. Neurology 2006; 66(1): 108-11.
[http://dx.doi.org/10.1212/01.wnl.0000191360.08881.12] [PMID: 16401857]
[32]
Dumanchin C, Tournier I, Martin C, et al. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat 2006; 27(10): 1063-3.
[http://dx.doi.org/10.1002/humu.9458] [PMID: 16941492]
[33]
Ikeuchi T, Kaneko H, Miyashita A, et al. Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord 2008; 26(1): 43-9.
[http://dx.doi.org/10.1159/000141483] [PMID: 18587238]
[34]
Wanngren J, Frånberg J, Svensson AI, et al. The large hydrophilic loop of presenilin 1 is important for regulating gamma secretase complex assembly and dictating the amyloid beta peptide (Abeta) Profile without affecting Notch processing. J Biol Chem 2010; 285(12): 8527-36.
[http://dx.doi.org/10.1074/jbc.M109.055590] [PMID: 20106965 ]

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