美國(guó)北加州大學(xué)醫(yī)學(xué)院的Benjamin Philpot等人近日《自然》（Nature）雜志發(fā)表論文稱，抗腫瘤藥拓?fù)洚悩?gòu)酶I抑制劑可激活一個(gè)沉默的名為Ube3a的父性等位基因,，該發(fā)現(xiàn)將有利于治療安琪兒綜合征。
安琪兒綜合征（或稱天使人綜合征）在1965年被首次描述，其特點(diǎn)為跳躍式運(yùn)動(dòng),、抽搐,、學(xué)習(xí)障礙、及頻繁發(fā)笑,，約每15000名新生兒中便可出現(xiàn)一名安琪兒綜合征患兒,。而現(xiàn)有的治療手段都只是對(duì)癥治療，無法從根本上改變患者的生存狀況,。
UBE3A 基因負(fù)責(zé)編碼UBE3A 蛋白,，該蛋白在調(diào)節(jié)非必須蛋白的降解和神經(jīng)系統(tǒng)的發(fā)育中起重要作用。正常人體內(nèi)有該基因的母性和父性等位基因,，在發(fā)育過程中父性等位基因被關(guān)閉,，僅有母性等位基因表達(dá)并參與上述調(diào)節(jié)過程。而在安琪兒綜合征患者體內(nèi),，該基因的母性等位基因發(fā)生突變或缺失,，導(dǎo)致其無法產(chǎn)生UBE3A蛋白。
因此Benjamin Philpot和Mark Zylka等設(shè)計(jì)了實(shí)驗(yàn)來研究如果UBE3A的父性等位基因被激活,，是否會(huì)產(chǎn)生UBE3A蛋白質(zhì),，從而達(dá)到治療安琪兒綜合征的目的。
在試驗(yàn)了約2300余種化合物后,，研究者發(fā)現(xiàn)抗腫瘤藥拓?fù)洚悩?gòu)酶I抑制劑可激活該基因,。拓?fù)洚悩?gòu)酶在DNA復(fù)制期間結(jié)合于DNA分子，以幫助其復(fù)制,，拓?fù)洚悩?gòu)酶抑制劑可抑制拓?fù)洚悩?gòu)酶與DNA分子的分離,，最終破壞該DNA。
該藥物激活父性Ube3a等位基因的機(jī)制尚不明確,，但研究者指出,，該作用或許與拓?fù)洚悩?gòu)酶I抑制劑可降低反轉(zhuǎn)錄基因Ube3a-ATS的表達(dá)有關(guān)，該反轉(zhuǎn)錄基因可阻斷Ube3a基因的表達(dá),。
隨后,，研究者給小鼠注射了一種拓?fù)洚悩?gòu)酶I抑制劑--拓?fù)涮婵担⒂^察Ube3a基因在該小鼠神經(jīng)細(xì)胞中的表達(dá),。結(jié)果發(fā)現(xiàn)該父性等位基因被激活,，并持續(xù)了長(zhǎng)達(dá)12周的時(shí)間。
作者稱,，該發(fā)現(xiàn)或?qū)榘茬鲀壕C合征及其他一些神經(jīng)發(fā)育性疾病的治療帶來新的希望,。（生物谷bioon.com）
doi:10.1038/nature10726
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Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons
Hsien-Sung Huang, John A. Allen, Angela M. Mabb, Ian F. King, Jayalakshmi Miriyala, Bonnie Taylor-Blake, Noah Sciaky, J. Walter Dutton, Hyeong-Min Lee, Xin Chen, Jian Jin, Arlene S. Bridges, Mark J. Zylka, Bryan L. Roth & Benjamin D. Philpot.
Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A)1, 2, 3. In neurons, the paternal allele of UBE3A is intact but epigenetically silenced4, 5, 6, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein7, 8. Using an unbiased, high-content screen in primary cortical neurons from mice, we identify twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsilence the paternal Ube3a allele. These drugs included topotecan, irinotecan, etoposide and dexrazoxane (ICRF-187). At nanomolar concentrations, topotecan upregulated catalytically active UBE3A in neurons from maternal Ube3a-null mice. Topotecan concomitantly downregulated expression of the Ube3a antisense transcript that overlaps the paternal copy of Ube3a9, 10, 11. These results indicate that topotecan unsilences Ube3a in cis by reducing transcription of an imprinted antisense RNA. When administered in vivo, topotecan unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum and spinal cord. Paternal expression of Ube3a remained elevated in a subset of spinal cord neurons for at least 12?weeks after cessation of topotecan treatment, indicating that transient topoisomerase inhibition can have enduring effects on gene expression. Although potential off-target effects remain to be investigated, our findings suggest a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome.
