2012年8月11日 訊 /生物谷BIOON/ --近日，來自加州大學(xué)戴維斯分校精神研究所的研究人員發(fā)現(xiàn)了一種缺陷性基因如何引發(fā)大腦改變,，進(jìn)而導(dǎo)致產(chǎn)生孤獨(dú)癥的非典型社會行為,。這就為開發(fā)治療孤獨(dú)癥的藥物提供了一個新型的靶點(diǎn)。相關(guān)研究成果刊登在了8月10日的國際雜志PLoS One上,。
前期研究表明在孤獨(dú)癥兒童中,，這種基因是缺陷的，但是其在大腦神經(jīng)元上的效應(yīng)卻不得而知,。這項(xiàng)以小鼠為研究對象的新研究揭示了基因的異?；顒涌梢云茐纳窠?jīng)元的能量利用。這種有害的改變加上非社交行為將會延長孤獨(dú)癥患者的反復(fù)行為,。
許多基因和環(huán)境因子都和孤獨(dú)癥有關(guān),，但是這項(xiàng)研究指出了某個基因的缺失如何觸發(fā)神經(jīng)學(xué)行為的發(fā)生。理解這種機(jī)制將為開發(fā)新型藥物提供方法,。研究者Giulivi表示,，這種基因的缺失將會破壞神經(jīng)元的能量利用。在小鼠實(shí)驗(yàn)中,，研究者發(fā)現(xiàn)名為pten基因如果被修飾就將引發(fā)神經(jīng)元缺少所需的pten蛋白質(zhì)的量,，研究者對小鼠中功能失常的線粒體進(jìn)行了4-6周的檢測。
從20周到29周,，線粒體中的DNA損傷以及功能的破壞明顯增加了,，這段時間內(nèi),，小鼠開始避免與其同類接觸，并且開始其重復(fù)性的動作行為,。缺乏單獨(dú)基因的小鼠既不表現(xiàn)出線粒體功能異常也不表現(xiàn)出行為問題,。
研究者指出，當(dāng)pten基因缺陷,，其蛋白質(zhì)可以和與p53蛋白質(zhì)相互作用來緩沖神經(jīng)元的能量產(chǎn)生,，這種嚴(yán)重的壓力會導(dǎo)致線粒體DNA的改變以及小腦、海馬體能量產(chǎn)生水平的異常,。以前pten的突變被證實(shí)和阿爾茲海默癥相關(guān),。這項(xiàng)新的研究表明，當(dāng)pten蛋白不充足的時候,，其和p53的反應(yīng)會引發(fā)其它蛋白質(zhì)的缺乏和缺陷,，這在孤獨(dú)癥患者中是已經(jīng)發(fā)現(xiàn)的。
相關(guān)研究由自比自閉癥基因會提供支持,。（生物谷Bioon.com）
編譯自：Research Shows Gene Defect's Role in Autism-Like Behavior
doi:10.1371/journal.pone.0042504
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PMID:
Mitochondrial Dysfunction in Pten Haplo-Insufficient Mice with Social Deficits and Repetitive Behavior: Interplay between Pten and p53
Eleonora Napoli1, Catherine Ross-Inta1, Sarah Wong1, Connie Hung1, Yasuko Fujisawa1, Danielle Sakaguchi1, James Angelastro1, Alicja Omanska-Klusek1, Robert Schoenfeld1, Cecilia Giulivi1,2*
Etiology of aberrant social behavior consistently points to a strong polygenetic component involved in fundamental developmental pathways, with the potential of being enhanced by defects in bioenergetics. To this end, the occurrence of social deficits and mitochondrial outcomes were evaluated in conditional Pten (Phosphatase and tensin homolog) haplo-insufficient mice, in which only one allele was selectively knocked-out in neural tissues. Pten mutations have been linked to Alzheimer's disease and syndromic autism spectrum disorders, among others. By 4–6 weeks of age, Pten insufficiency resulted in the increase of several mitochondrial Complex activities (II–III, IV and V) not accompanied by increases in mitochondrial mass, consistent with an activation of the PI3K/Akt pathway, of which Pten is a negative modulator. At 8–13 weeks of age, Pten haplo-insufficient mice did not show significant behavioral abnormalities or changes in mitochondrial outcomes, but by 20–29 weeks, they displayed aberrant social behavior (social avoidance, failure to recognize familiar mouse, and repetitive self-grooming), macrocephaly, increased oxidative stress, decreased cytochrome c oxidase (CCO) activity (50%) and increased mtDNA deletions in cerebellum and hippocampus. Mitochondrial dysfunction was the result of a downregulation of p53-signaling pathway evaluated by lower protein expression of p21 (65% of controls) and the CCO chaperone SCO2 (47% of controls), two p53-downstream targets. This mechanism was confirmed in Pten-deficient striatal neurons and, HCT 116 cells with different p53 gene dosage. These results suggest a unique pathogenic mechanism of the Pten-p53 axis in mice with aberrant social behavior: loss of Pten (via p53) impairs mitochondrial function elicited by an early defective assembly of CCO and later enhanced by the accumulation of mtDNA deletions. Consistent with our results, (i) SCO2 deficiency and/or CCO activity defects have been reported in patients with learning disabilities including autism and (ii) mutated proteins in ASD have been found associated with p53-signaling pathways.
