Increased 3-O-sulfated heparan sulfate in Alzheimer's disease brain is associated with genetic risk gene HS3ST1.

Increased 3-O-sulfated heparan sulfate in Alzheimer's disease brain is associated with genetic risk gene HS3ST1.
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在阿尔茨海默氏病大脑中,硫酸盐硫酸盐硫酸盐的增加与遗传风险基因HS3ST1有关。

DOI:
10.1126/sciadv.adf6232
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发表时间:
2023-05-26
期刊:
影响因子:
13.6
通讯作者:
Liu, Jian
Liu, Jian
中科院分区:
综合性期刊1区
文献类型:
--
作者:
Wang, Zhangjie;Patel, Vaishali N.;Song, Xuehong;Xu, Yongmei;Kaminski, Andrea M.;Doan, Vivien Uyen;Su, Guowei;Liao, Yien;Mah, Dylan;Zhang, Fuming;Pagadala, Vijayakanth;Wang, Chunyu;Pedersen, Lars C.;Wang, Lianchun;Hoffman, Matthew P.;Gearing, Marla;Liu, Jian

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HS3ST1是一种与阿尔茨海默病(AD)相关的遗传风险基因,在患者中过表达,但其如何促进疾病进展尚不清楚。我们报道了用LC-MS/MS方法分析AD和其他牛头病的脑硫酸肝素(HS)。AD组特异性3- o -硫酸盐HS升高7倍(n = 14, P < 0.0005)。通过对重组硫转移酶修饰的HS和基因敲除小鼠HS的分析,发现特异性的3- o -硫酸化HS是由HS3ST1基因编码的3- o -硫转移酶异构体1 (3-OST-1)合成的。携带特定3- o -硫酸化结构域的合成十四聚糖(14-mer)比没有该结构域的14-mer对tau内化的抑制更强,这表明3- o -硫酸化HS在tau细胞摄取中起作用。我们的研究结果表明,HS3ST1基因的过表达可能会增强tau病理的传播,揭示了以前未发现的AD治疗靶点。硫酸肝素亚群是一个基于甘聚糖的阿尔茨海默病风险标志物。
HS3ST1 is a genetic risk gene associated with Alzheimer’s disease (AD) and overexpressed in patients, but how it contributes to the disease progression is unknown. We report the analysis of brain heparan sulfate (HS) from AD and other tauopathies using a LC-MS/MS method. A specific 3-O-sulfated HS displayed sevenfold increase in the AD group (n = 14, P < 0.0005). Analysis of the HS modified by recombinant sulfotransferases and HS from genetic knockout mice revealed that the specific 3-O-sulfated HS is made by 3-O-sulfotransferase isoform 1 (3-OST-1), which is encoded by the HS3ST1 gene. A synthetic tetradecasaccharide (14-mer) carrying the specific 3-O-sulfated domain displayed stronger inhibition for tau internalization than a 14-mer without the domain, suggesting that the 3-O-sulfated HS is used in tau cellular uptake. Our findings suggest that the overexpression of HS3ST1 gene may enhance the spread of tau pathology, uncovering a previously unidentified therapeutic target for AD. A specific heparan sulfate subpopulation is a glycan-based risk marker for Alzheimer’s disease.
DOI: 10.1038/s41588-022-01024-z
发表时间: 2022-04
期刊: NATURE GENETICS
影响因子: 30.8
作者:
Bellenguez, Celine;Kucukali, Fahri;Jansen, Iris E.;Kleineidam, Luca;Moreno-Grau, Sonia;Amin, Najaf;Naj, Adam C.;Campos-Martin, Rafael;Grenier-Boley, Benjamin;Andrade, Victor;Holmans, Peter A.;Boland, Anne;Damotte, Vincent;van der Lee, Sven J.;Costa, Marcos R.;Kuulasmaa, Teemu;Yang, Qiong;De Rojas, Itziar;Bis, Joshua C.;Yaqub, Amber;Prokic, Ivana;Chapuis, Julien;Ahmad, Shahzad;Giedraitis, Vilmantas;Aarsland, Dag;Garcia-Gonzalez, Pablo;Abdelnour, Carla;Alarcon-Martin, Emilio;Alcolea, Daniel;Alegret, Montserrat;Alvarez, Ignacio;Alvarez, Victoria;Armstrong, Nicola J.;Tsolaki, Anthoula;Antunez, Carmen;Appollonio, Ildebrando;Arcaro, Marina;Archetti, Silvana;Arias Pastor, Alfonso;Arosio, Beatrice;Athanasiu, Lavinia;Bailly, Henri;Banaj, Nerisa;Baquero, Miquel;Barral, Sandra;Beiser, Alexa;Pastor, Ana Belen;Below, Jennifer E.;Benchek, Penelope;Benussi, Luisa;Berr, Claudine;Besse, Celine;Bessi, Valentina;Binetti, Giuliano;Bizarro, Alessandra;Blesa, Rafael;Boada, Merce;Boerwinkle, Eric;Borroni, Barbara;Boschi, Silvia;Bossu, Paola;Brathen, Geir;Bressler, Jan;Bresner, Catherine;Brodaty, Henry;Brookes, Keeley J.;Ignacio Brusco, Luis;Buiza-Rueda, Dolores;Burger, Katharina;Burholt, Vanessa;Bush, William S.;Calero, Miguel;Cantwell, Laura B.;Chene, Genevieve;Chung, Jaeyoon;Cuccaro, Michael L.;Cecchetti, Roberta;Cervera-Carles, Laura;Charbonnier, Camille;Chen, Hung-Hsin;Chillotti, Caterina;Ciccone, Simona;Claassen, Jurgen A. 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DOI: 10.1021/acs.biochem.9b00838
发表时间: 2020-09-01
期刊: BIOCHEMISTRY
影响因子: 2.9
作者:
Dhurandhare, Vijay Manohar;Pagadala, Vijayakanth;Liu, Jian
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发表时间: 2003-04-01
影响因子: 15.9
作者:
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发表时间: 2020-03-01
影响因子: 14
作者:
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发表时间: 2018-04-23
期刊: Scientific reports
影响因子: 4.6
作者:
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通讯作者: Kosik KS