Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.
Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.
复制标题
DOI：
10.1371/journal.pbio.1001923
复制
发表时间：
2014-08
期刊：
影响因子：
9.8
通讯作者：
Lombroso PJ
中科院分区：
文献类型：
--
作者：
Xu J;Chatterjee M;Baguley TD;Brouillette J;Kurup P;Ghosh D;Kanyo J;Zhang Y;Seyb K;Ononenyi C;Foscue E;Anderson GM;Gresack J;Cuny GD;Glicksman MA;Greengard P;Lam TT;Tautz L;Nairn AC;Ellman JA;Lombroso PJ
这项研究发现了一种不寻常的硫基化学物质，它是酪氨酸磷酸酶步骤的一种新的和特异的抑制剂，并表明它可以改善阿尔茨海默病小鼠的认知功能。STEP(纹状体浓缩蛋白酪氨酸磷酸酶)是一种神经元特异性磷酸酶，调节N-甲基-D-天冬氨酸受体(NMDAR)和α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸受体(AMPAR)的转运，以及ERK1/2、p38、Fyn和PYK2活性。STEP在几种神经精神和神经退行性疾病中过度活跃，包括阿尔茨海默病(AD)。STEP活性的增加可能会扰乱突触功能，并导致AD的认知缺陷。缺乏STEP的AD小鼠恢复了突触体膜上谷氨酸受体的水平，并改善了认知功能，结果表明STEP是治疗AD的新靶点。在这里，我们描述了识别和表征小分子步长抑制剂的第一次大规模努力。我们鉴定了苯并五硫8-(trifluoromethyl)-1，2，3，4，5-benzopentathiepin-6-amine盐酸盐(称为TC-2153)为STEP的抑制剂，其IC50值为24.6nM。TC-2153代表了一类基于环状多硫化物药效团的新型PTP抑制剂，该药效团与催化半胱氨酸形成可逆的共价键。在基于细胞的二次分析中，TC-2153增加了STEP底物ERK1/2、PYK2和GluN2B的酪氨酸磷酸化，并且在皮质培养中没有表现出毒性。在野生型(WT)和STEP基因敲除(KO)的皮质细胞中以及在WT和STEP KO小鼠体内进行的验证和特异性实验表明，与高度同源的酪氨酸磷酸酶相比，STEP抑制剂具有特异性。此外，TC-2153改善了6个月和12个月大的三重转基因AD(3xTg-AD)小鼠在几个认知任务中的认知功能，而β淀粉样蛋白和磷酸化tau水平没有变化。最近的一系列研究发现，纹状体浓缩蛋白酪氨酸磷酸酶(STEP)在几种不同的神经精神和神经退行性疾病中水平升高，包括阿尔茨海默病、脆性X综合征和精神分裂症。STEP通常反对突触加强的发展，这些异常高水平的活性STEP通过从一些蛋白质中移除磷酸基团来扰乱突触功能，包括几个谷氨酸受体和激酶。去磷酸化导致谷氨酸受体内部化和激酶失活--这些事件扰乱了记忆的巩固。在这里，我们确定苯并五硫8-(trifluoromethyl)-1，2，3，4，5-benzopentathiepin-6-amine盐酸盐(称为TC-2153)是一种新型的STEP抑制剂。结果表明，TC-2153的作用机制是在抑制剂和STEP的催化半胱氨酸残基之间形成可逆的共价键，并证明了TC-2153的体内外活性。与其他几种酪氨酸磷酸酶相比，TC-2153显示出对STEP的特异性，并且对培养的神经元没有毒性。重要的是，该化合物逆转了阿尔茨海默病小鼠模型的认知缺陷，其方式不涉及常见病理迹象(p-tau和β-淀粉样蛋白)的变化。
This study identifies an unusual sulfur-based chemical as a novel and specific inhibitor of the tyrosine phosphatase STEP and shows that it can improve the cognitive function of a mouse model of Alzheimer's disease. STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels. A series of recent studies have found that the levels of the enzyme striatal-enriched protein tyrosine phosphatase (STEP) are raised in several different neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, fragile X syndrome, and schizophrenia. STEP normally opposes the development of synaptic strengthening, and these abnormally high levels of active STEP disrupt synaptic function by removing phosphate groups from a number of proteins, including several glutamate receptors and kinases. Dephosphorylation results in internalization of the glutamate receptors and inactivation of the kinases—events that disrupt the consolidation of memories. Here we identify the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as a novel inhibitor of STEP. We show that the mechanism of action involves the formation of a reversible covalent bond between the inhibitor and the catalytic cysteine residue of STEP, and we demonstrate the activity of TC-2153 both in vitro and in vivo. TC-2153 shows specificity towards STEP compared to several other tyrosine phosphatases and shows no toxicity to cultured neurons. Importantly, the compound reversed cognitive deficits in a mouse model of Alzheimer's disease in a way that did not involve changes in the usual pathological signs (p-tau and beta-amyloid).
登录
查看更多内容
DOI：
10.1111/j.1601-183x.2012.00781.x
发表时间：
2012-07
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Goebel-Goody SM;Wilson-Wallis ED;Royston S;Tagliatela SM;Naegele JR;Lombroso PJ
通讯作者：
Lombroso PJ
影响因子：
4.8
作者：
Groen, A;Lemeer, S;den Hertog, J
通讯作者：
den Hertog, J
DOI：
10.1073/pnas.1017856108
发表时间：
2011-04-19
影响因子：
11.1
作者：
Hicklin, Tianna R.;Wu, Peter H.;Browning, Michael D.
通讯作者：
Browning, Michael D.
影响因子：
4.7
作者：
Darcq E;Hamida SB;Wu S;Phamluong K;Kharazia V;Xu J;Lombroso P;Ron D
通讯作者：
Ron D
影响因子：
4.8
作者：
Chen, Yi-Yun;Chu, Hsing-Mao;Meng, Tzu-Ching
通讯作者：
Meng, Tzu-Ching