諸如阿爾茨海默氏病,、多發(fā)性硬化癥與散發(fā)性克—雅氏?。ǒ偱２,。┑绕茐纳窠?jīng)細(xì)胞的疾病，對(duì)科學(xué)家來(lái)說(shuō)始終難以捉摸,，更是難以治愈,。最近，美國(guó)密歇根大學(xué)科研人員發(fā)現(xiàn)了一種不知名的信號(hào)分子與神經(jīng)細(xì)胞健康之間的聯(lián)系,，這有望解釋神經(jīng)細(xì)胞退化的原因,。該科研成果發(fā)表在近期出版的《美國(guó)國(guó)家科學(xué)院院刊》雜志上。
在該項(xiàng)研究中,，美國(guó)生命科學(xué)學(xué)院教授洛伊斯·威斯曼及其助手將這種信號(hào)分子與腦部大量的神經(jīng)細(xì)胞退化聯(lián)系起來(lái),。這種被稱為PI(3,5)P2（磷脂酰肌醇-3,5-二磷酸的簡(jiǎn)稱）的分子存在于所有細(xì)胞中,，是一種濃度很低的脂質(zhì),。
信號(hào)脂質(zhì)PI(3,5)P2是生物信息系統(tǒng)的一部分，這種信息系統(tǒng)不僅可感知細(xì)胞外的變化,，也可促進(jìn)細(xì)胞內(nèi)部活動(dòng)以使細(xì)胞適應(yīng)該變化,，是一類非常獨(dú)特的脂質(zhì)，承擔(dān)著信號(hào)分子的特殊使命,。而產(chǎn)生脂質(zhì)的酶由酵母基因FIG4與VAC14基因控制,，這兩種基因不僅存在于酵母菌，也同樣存在于老鼠和人類體內(nèi),。VAC14是對(duì)PI(3,5)P2濃度進(jìn)行編碼的基因,。威斯曼發(fā)現(xiàn)，缺乏VAC14的老鼠神經(jīng)系統(tǒng)嚴(yán)重退化,，而這種退化看起來(lái)類似于那些FIG4發(fā)生突變的老鼠的神經(jīng)細(xì)胞的退化,，一旦VAC14基因被移除，很多神經(jīng)元細(xì)胞的本體內(nèi)就會(huì)出現(xiàn)空洞空間,，大腦則呈現(xiàn)海綿狀,。
威斯曼表示，PI(3,5)P2對(duì)于神經(jīng)系統(tǒng)細(xì)胞的存活起了關(guān)鍵性作用,，較低濃度的PI(3,5)P2可導(dǎo)致重度的神經(jīng)細(xì)胞退化,，這一發(fā)現(xiàn)預(yù)示著可以更好地研究如阿爾茨海默氏病等神經(jīng)細(xì)胞退化性疾病的療法。（科技日?qǐng)?bào)）
原始出處:
Published online before print October 23, 2007, 10.1073/pnas.0702275104
PNAS | October 30, 2007 | vol. 104 | no. 44 | 17518-17523
Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice
Yanling Zhang*,, Sergey N. Zolov*, Clement Y. Chow, Shalom G. Slutsky, Simon C. Richardson¶, Robert C. Piper¶, Baoli Yang||, Johnathan J. Nau, Randal J. Westrick, Sean J. Morrison, Miriam H. Meisler, and Lois S. Weisman*,**,
*Life Sciences Institute, Department of Human Genetics, **Department of Cellular and Developmental Biology, and Howard Hughes Medical Institute and Department of Internal Medicine and Center for Stem Cell Biology, University of Michigan, Ann Arbor, MI 48109; and Departments of Biochemistry, ¶Physiology, and ||Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242
Edited by Pietro V. De Camilli, Yale University School of Medicine, New Haven, CT, and approved September 17, 2007 (received for review March 12, 2007)
The signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), likely functions in multiple signaling pathways. Here, we report the characterization of a mouse mutant lacking Vac14, a regulator of PI(3,5)P2 synthesis. The mutant mice exhibit massive neurodegeneration, particularly in the midbrain and in peripheral sensory neurons. Cell bodies of affected neurons are vacuolated, and apparently empty spaces are present in areas where neurons should be present. Similar vacuoles are found in cultured neurons and fibroblasts. Selective membrane trafficking pathways, especially endosome-to-TGN retrograde trafficking, are defective. This report, along with a recent report on a mouse with a null mutation in Fig4, presents the unexpected finding that the housekeeping lipid, PI(3,5)P2, is critical for the survival of neural cells.
Fab1 | PIKfyve | PtdInsI(3,5)P2 | spongiform | endosomal traffic
