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Increased 3- O -sulfated heparan sulfate in Alzheimer’s disease brain is associated with genetic risk gene HS3ST1
Science Advances ( IF 11.7 ) Pub Date : 2023-05-26 , DOI: 10.1126/sciadv.adf6232
Zhangjie Wang 1 , Vaishali N Patel 2 , Xuehong Song 3 , Yongmei Xu 1 , Andrea M Kaminski 4 , Vivien Uyen Doan 1 , Guowei Su 5 , Yien Liao 1 , Dylan Mah 6 , Fuming Zhang 6 , Vijayakanth Pagadala 5 , Chunyu Wang 6 , Lars C Pedersen 4 , Lianchun Wang 3 , Matthew P Hoffman 2 , Marla Gearing 7 , Jian Liu 1
Affiliation  

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.

中文翻译:


阿尔茨海默病大脑中 3-O-硫酸化硫酸乙酰肝素的增加与遗传风险基因 HS3ST1 相关



HS3ST1 是一种与阿尔茨海默病 (AD) 相关的遗传风险基因,在患者中过度表达,但它如何促进疾病进展尚不清楚。我们报告了使用 LC-MS/MS 方法对 AD 和其他 tau蛋白病的脑硫酸乙酰肝素 (HS) 进行的分析。 AD 组中特定的 3-O-硫酸化 HS 显示增加了七倍(n = 14,P < 0.0005)。对重组磺基转移酶修饰的 HS 和来自基因敲除小鼠的 HS 的分析表明,特定的 3-O-硫酸化 HS 是由 3-O-磺基转移酶亚型 1 (3-OST-1) 产生的,该亚型由 HS3ST1 基因编码。携带特定 3-O-硫酸化结构域的合成十四糖(14-mer)对 tau 内化表现出比没有该结构域的 14-mer 更强的抑制作用,表明 3-O-硫酸化 HS 用于 tau 细胞摄取。我们的研究结果表明,HS3ST1 基因的过度表达可能会增强 tau 病理学的传播,从而揭示了先前未知的 AD 治疗靶点。
更新日期:2023-05-26
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