A PIN1 polymorphism that prevents its suppression by AP4 associates with delayed onset of Alzheimer's disease.
A PIN1 polymorphism that prevents its suppression by AP4 associates with delayed onset of Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2010.05.018
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发表时间：
2012-04
影响因子：
4.2
通讯作者：
Lu KP
中科院分区：
文献类型：
--
作者：
Ma SL;Tang NL;Tam CW;Lui VW;Lam LC;Chiu HF;Driver JA;Pastorino L;Lu KP
阿尔茨海默病（AD）是最常见的痴呆形式，其特征是存在由tau和源自淀粉样前体蛋白（APP）的淀粉样β肽（Aβ）老年斑组成的神经原纤维缠结。Pin1是一种独特的脯氨酸异构酶，已被证明通过作用于磷酸化的tau和APP来抑制缠结形成和淀粉样变性APP加工，从而防止年龄依赖性神经变性。在这里，我们报告了Pin1启动子中的功能多态性rs2287839，该多态性与中国人群中晚发性AD的平均发病年龄（AAO）延迟3年显着相关。更重要的是，Pin1多态性rs2287839位于脑选择性转录因子AP4 （CAGCTG）的共识结合基序内，几乎完全消除了AP4结合和抑制Pin1启动子的能力，如染色质免疫沉淀、电泳迁移率转移和启动子荧光素酶测定。此外，AP4的过表达或敲低分别导致内源性Pin1水平降低80%或增加两倍。因此，AP4是一种新的Pin1表达的转录抑制因子，而本研究中发现的阻止这种抑制的Pin1启动子SNP与AD的延迟发病有关。这些结果表明AP4对Pin1的调控在AD的AAO中起着关键作用，可能是延缓AD发病的新的治疗靶点。
Alzheimer’s disease (AD), the most common form of dementia, is characterized by the presence of neurofibrillary tangles composed of tau and senile plaques of amyloid-beta peptides (Aβ) derived from amyloid precursor protein (APP). Pin1 is a unique prolyl isomerase that has been shown to protect against age-dependent neurodegeneration by acting on phosphorylated tau and APP to suppress tangle formation and amyloidogenic APP processing. Here we report a functional polymorphism, rs2287839, in the Pin1 promoter that is significantly associated with a 3-year delay in the average age-at-onset (AAO) of late-onset AD in a Chinese population. More significantly, the Pin1 polymorphism rs2287839 is located within the consensus binding motif for the brain-selective transcription factor, AP4 (CAGCTG) and almost completely abolishes the ability of AP4 to bind and suppress the Pin1 promoter, as shown by chromatin immunoprecipitation, electrophoretic mobility shift assay and promoter luciferase assay. Moreover, overexpression or knockdown of AP4 resulted in an 80% reduction or two-fold increase in endogenous Pin1 levels, respectively. Thus, AP4 is a novel transcriptional repressor of Pin1 expression and the Pin1 promoter SNP identified in this study that prevents such suppression is associated with delayed onset of AD. These results indicate that regulation of Pin1 by AP4 plays a critical role in determining AAO of AD and might be a novel therapeutic target to delay the onset of AD.
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DOI：
10.1002/ajmg.b.30689
发表时间：
2008-09-05
影响因子：
2.8
作者：
Dickson, M. Ryan;Li, Jian;Wiener, Howard W.;Perry, Rodney T.;Blacker, Deborah;Bassett, Susan S.;Go, Rodney C. P.
通讯作者：
Go, Rodney C. P.
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
2.5
作者：
Lambert, JC;Bensemain, F;Amouyel, P
通讯作者：
Amouyel, P
影响因子：
2.5
作者：
Kohnken, R;Buerger, K;Hampel, H
通讯作者：
Hampel, H
影响因子：
14.9
作者：
Heinemeyer, T;Wingender, E;Kolchanov, NA
通讯作者：
Kolchanov, NA