巴塞羅那自治大學(xué)（INC-UAB）神經(jīng)科學(xué)研究所的研究人員發(fā)現(xiàn)Nurr1基因在神經(jīng)元存活中所發(fā)揮的基本作用與突觸活動(dòng)有關(guān),。這一發(fā)現(xiàn)發(fā)表在Journal of Biological Chemistry雜志上,，這項(xiàng)研究幫助科學(xué)家了解神經(jīng)連接的變化，神經(jīng)連接變化是已知的導(dǎo)致早期認(rèn)知功能障礙和阿爾茨海默氏病的神經(jīng)退行性疾病的特點(diǎn),。
在大腦的發(fā)育過(guò)程中，如果神經(jīng)元之間不建立必要的連接的話,，成千上萬(wàn)的神經(jīng)元會(huì)死,。調(diào)節(jié)神經(jīng)元存活和死亡的過(guò)程對(duì)成人大腦的腦連接的形成很重要。
然而,，突觸活動(dòng)對(duì)這些神經(jīng)元存活的影響不僅限于發(fā)育中的大腦中,，它也是成人大腦發(fā)育的根本。突觸活動(dòng)喪失的話,，神經(jīng)退行性疾病如阿爾茨海默氏癥患者的認(rèn)知會(huì)受損,，這些疾病中也會(huì)有神經(jīng)元死亡。盡管這一進(jìn)程的重要性,，但目前還沒(méi)有明確突觸活動(dòng)調(diào)控神經(jīng)元存活的分子機(jī)制,。
UAB的神經(jīng)科學(xué)研究所研究員José Rodríguez lvarez等發(fā)現(xiàn)突觸活動(dòng)調(diào)控了一個(gè)基因以及神經(jīng)元的存活。通過(guò)大規(guī)模的基因活性分析,，研究人員發(fā)現(xiàn)了數(shù)十個(gè)基因被突觸活動(dòng)調(diào)控,。研究表明在所有的基因中，Nurr1基因在神經(jīng)元的生存發(fā)揮的了關(guān)鍵作用,。研究人員發(fā)現(xiàn),，當(dāng)這一基因的活性被沉默時(shí)，神經(jīng)元會(huì)死亡,。（生物谷：Bioon.com）
doi:10.1074/jbc.M111.272427
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Nurr1 Protein Is Required for N-Methyl-D-aspartic Acid (NMDA) Receptor-mediated Neuronal Survival
B. Barneda-Zahonero, J.-M. Servitja, N. Badiola, A. J. Minano-Molina, R. Fado, C. A. Saura, J. Rodriguez-Alvarez
NMDA receptor (NMDAR) stimulation promotes neuronal survival during brain development. Cerebellar granule cells (CGCs) need NMDAR stimulation to survive and develop. These neurons differentiate and mature during its migration from the external granular layer to the internal granular layer, and lack of excitatory inputs triggers their apoptotic death. It is possible to mimic this process in vitro by culturing CGCs in low KCl concentrations (5 mm) in the presence or absence of NMDA. Using this experimental approach, we have obtained whole genome expression profiles after 3 and 8 h of NMDA addition to identify genes involved in NMDA-mediated survival of CGCs. One of the identified genes was Nurr1, a member of the orphan nuclear receptor subfamily Nr4a. Our results report a direct regulation of Nurr1 by CREB after NMDAR stimulation. ChIP assay confirmed CREB binding to Nurr1 promoter, whereas CREB shRNA blocked NMDA-mediated increase in Nurr1 expression. Moreover, we show that Nurr1 is important for NMDAR survival effect. We show that Nurr1 binds to Bdnf promoter IV and that silencing Nurr1 by shRNA leads to a decrease in brain-derived neurotrophic factor (BDNF) protein levels and a reduction of NMDA neuroprotective effect. Also, we report that Nurr1 and BDNF show a similar expression pattern during postnatal cerebellar development. Thus, we conclude that Nurr1 is a downstream target of CREB and that it is responsible for the NMDA-mediated increase in BDNF, which is necessary for the NMDA-mediated prosurvival effect on neurons.
