美國(guó)轉(zhuǎn)譯遺傳研究所（TGen）的一科學(xué)小組發(fā)現(xiàn)了3種可引發(fā)tao蛋白功能障礙的激酶（從高能供體分子轉(zhuǎn)移磷酸基團(tuán)到特定靶分子的酶）,，正是這3種激酶阻斷了大腦細(xì)胞間的連接,，進(jìn)而導(dǎo)致了與阿爾茨海默病相關(guān)的記憶缺失問(wèn)題,。研究人員認(rèn)為,，該發(fā)現(xiàn)有助于開發(fā)出治療阿爾茨海默病的新藥。相關(guān)論文發(fā)表在近期出版的《BMC基因組學(xué)》雜志上,。
tao蛋白是一種對(duì)神經(jīng)細(xì)胞間微管連接橋的形成起重要作用的蛋白。這種微管橋猶如神經(jīng)細(xì)胞內(nèi)的“骨架”,，支持著突觸連接,，使神經(jīng)細(xì)胞間如計(jì)算機(jī)電路一樣能彼此溝通,。如果tao蛋白功能出現(xiàn)障礙，將導(dǎo)致神經(jīng)細(xì)胞間無(wú)法再相互聯(lián)系,，從而嚴(yán)重影響人的認(rèn)知,，即思考和推理能力。
TGen神經(jīng)變性研究小組助理研究員特拉維斯·鄧克利博士撰文指出,，在正常情況下,，激酶通過(guò)增加磷酸來(lái)調(diào)節(jié)tao蛋白，這個(gè)被叫做tao蛋白磷酸化的過(guò)程可使微管解開后再綁定,，使神經(jīng)細(xì)胞間能夠相互連接,，從而促進(jìn)人的記憶的形成和保持。
然而,，有時(shí)tao蛋白會(huì)過(guò)度磷酸化,，微管橋會(huì)被拆解，導(dǎo)致神經(jīng)原纖維纏結(jié),。而神經(jīng)原纖維纏結(jié)是阿爾茨海默病的典型病理特征之一,。
該研究小組使用一種叫做siRNA的分子工具，對(duì)人體細(xì)胞內(nèi)所有已知的和理論推理出的572個(gè)激酶進(jìn)行了復(fù)雜的測(cè)試,，最終確定了26個(gè)與tao蛋白磷酸化有關(guān)的激酶,，而其中的3種激酶EIF2AK2、DYRK1A和AKAP13導(dǎo)致了tao蛋白的過(guò)度磷酸化,，從而永久地拆解了微管橋,。
TGen神經(jīng)遺傳學(xué)分部的臨床主任，同時(shí)也是巴納阿爾茨海默病研究所執(zhí)行主任的埃里克·雷曼博士解釋說(shuō),，tao蛋白將神經(jīng)細(xì)胞內(nèi)的“骨架”結(jié)合在一起,，當(dāng)磷酸分子與tao蛋白粘合時(shí)，該“骨架”瓦解,，神經(jīng)細(xì)胞開始收回突觸分支并死亡,，導(dǎo)致記憶喪失和思考能力出現(xiàn)問(wèn)題。而通過(guò)siRNA,，研究人員就可斷定,，是哪一種蛋白促發(fā)了磷酸分子與tao蛋白的粘結(jié)。
雷曼稱,，這3種激酶現(xiàn)在或可成為蛋白抑制藥物的靶點(diǎn),。如果能開發(fā)出一種安全的、耐受性很好的治療神經(jīng)原纖維纏結(jié)的藥物,，將給阿爾茨海默病的治療帶來(lái)希望,。他們下一步的任務(wù)，就是要找到并確定使這3種激酶無(wú)效的藥物成分,。（生物谷Bioon.com）
生物谷推薦原始出處：
BMC Genomics 2010, 11:25doi:10.1186/1471-2164-11-25
High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation
David O Azorsa , RiLee H Robeson , Danielle Frost , Bessie Meechoovet , Gillian R Brautigam , Chad Dickey , Christian Beaudry , Gargi D Basu , David R Holz , Joseph A Hernandez , Kristen M Bisanz , Leslie Gwinn , Andrew Grover , Joseph Rogers , Eric M Reiman , Michael Hutton , Dietrich A Stephan , Spyro Mousses and Travis Dunckley
Background
Neurofibrillary tangles (NFT), a cardinal neuropathological feature of Alzheimer's disease (AD) that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments.
Results
We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 kinase 2 (EIF2AK2), the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and the A-kinase anchor protein 13 (AKAP13) on tau phosphorylation at serine 262. We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways.
Conclusions
These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.
