2012年10月10日 電 /生物谷BIOON/ --近日,，科學(xué)家在研究精神分裂癥發(fā)病分子機(jī)制中獲得了突破性進(jìn)展,，相關(guān)研究結(jié)果發(fā)表在10月10日出版的Journal of Neuroscience雜志上。這一發(fā)現(xiàn)可能引導(dǎo)研究人員開(kāi)發(fā)治療精神分裂癥的新治療方案,。
精神分裂癥的特點(diǎn)包括幻覺(jué),、學(xué)習(xí)和記憶能力退化等，這些癥狀通常出現(xiàn)在青春期后期或成年早期,。努力查明該疾病的發(fā)病原因是很復(fù)雜的,，因?yàn)檠芯坎⑽醋C實(shí)任何一個(gè)單一的基因突變與該疾病密切相關(guān)。但最近,，圣裘德兒童研究醫(yī)院Laurie Earls博士和他的同事通過(guò)研究一種罕見(jiàn)的遺傳性疾病22q11缺失綜合征發(fā)現(xiàn),，22q11缺失導(dǎo)致精神分裂癥的風(fēng)險(xiǎn)增加。
大約有30％的22q11缺失綜合征的人會(huì)患上精神分裂癥,，22q11缺失綜合征是精神分裂癥疾病最強(qiáng)的危險(xiǎn)因素之一。在以往研究22q11缺失的小鼠中,，Zakharenko研究小組發(fā)現(xiàn),，神經(jīng)細(xì)胞在大腦海馬學(xué)習(xí)和記憶中心功能中發(fā)生了變化，隨著年齡的增長(zhǎng)功能逐漸喪失,。在這項(xiàng)新研究中,，科學(xué)家證實(shí)了類似的分子變化在精神分裂癥患者中也存在，因此他們將目光聚集在促進(jìn)神經(jīng)細(xì)胞功能變化的基因上,。
在以前的研究中,，Zakharenko研究小組發(fā)現(xiàn),，異常神經(jīng)細(xì)胞之間的溝通以及認(rèn)知功能障礙與調(diào)節(jié)某些Serca2神經(jīng)細(xì)胞中鈣水平的蛋白質(zhì)升高有關(guān)。上述異?，F(xiàn)象只在22q11缺失的小鼠在隨著年齡的增長(zhǎng)過(guò)程中能檢測(cè)到,。在目前的研究中，研究人員發(fā)現(xiàn)基因Dgcr8變化可以解釋其中機(jī)制,，Dgcr8生成小分子RNA,，保持Serca2神經(jīng)細(xì)胞正常。如果沒(méi)有Dgcr8,，調(diào)節(jié)Serca2神經(jīng)細(xì)胞中鈣水平的蛋白質(zhì)升高,。在22q11缺失的動(dòng)物海馬回中加入這些基因Dgcr8分子，研究人員能夠恢復(fù)Serca2功能,，減少遺傳缺陷,。
研究人員還分析了精神分裂癥患者腦組織驗(yàn)尸報(bào)告，結(jié)果發(fā)現(xiàn)22q11未缺失的精神分裂癥患者Serca2功能也異常,。Zakharenko認(rèn)為這些數(shù)據(jù)表明Serca2可能是精神分裂癥的一種新的治療靶標(biāo),。（生物谷：Bioon.com）
doi:10.1523/JNEUROSCI.1312-12.2012
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Age-Dependent MicroRNA Control of Synaptic Plasticity in 22q11 Deletion Syndrome and Schizophrenia
Laurie R. Earls, R. Gaines Fricke, Jing Yu, Raymond B. Berry, et al.
The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5–3 Mb region of chromosome 22. It constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2), which is responsible for loading Ca2+ into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca2+ load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8+/? mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.
