德國(guó)科學(xué)家近日?qǐng)?bào)告說，他們查明了一種家族性帕金森氏癥的致病機(jī)理,，并發(fā)現(xiàn)了此病一種可能的治療靶點(diǎn),。
2003年科學(xué)家曾發(fā)現(xiàn)少數(shù)人的家族性帕金森氏癥是由他們攜帶的DJ－1基因變異引起的。但是迄今科學(xué)界對(duì)DJ－1了解并不多,。
德意志研究聯(lián)合會(huì)腦分子生理學(xué)研究中心科學(xué)家4日?qǐng)?bào)告說,，他們利用細(xì)胞內(nèi)折疊酶生物傳感器查明DJ－1蛋白存在于健康細(xì)胞的細(xì)胞質(zhì)溶質(zhì)中，并以同型二聚體的形式存在,。所謂同型二聚體，即兩個(gè)相同分子的形式與細(xì)胞膜和細(xì)胞器相關(guān)聯(lián),。這種蛋白的另一個(gè)功能是作為所謂“伴娘蛋白”與新合成的蛋白形成復(fù)合物并協(xié)助它正確折疊,。當(dāng)DJ－1基因發(fā)生最常見的“L166P”點(diǎn)突變時(shí)，DJ－1蛋白的亞細(xì)胞分布不僅會(huì)改變,，其同型二聚體化能力和“伴娘蛋白”功能也會(huì)被削弱,，由此會(huì)產(chǎn)生錯(cuò)誤折疊的蛋白，并最終導(dǎo)致神經(jīng)細(xì)胞壞死,。
與此同時(shí),，德國(guó)科學(xué)家還意外發(fā)現(xiàn)一種名為“BAG1”的蛋白可以與DJ－1蛋白結(jié)合，并能在后者變異的情況下恢復(fù)其同型二聚體化能力和“伴娘蛋白”功能,，從而能避免細(xì)胞壞死。這為將來科學(xué)家找到治療DJ－1基因變異引起的帕金森氏癥的辦法提供了一種可能性,。(生物谷Bioon.com)
更多閱讀
The Lancet Neuro.： 大腦植入電極治療帕金森氏癥效果佳
Nature Genetics：全基因組關(guān)聯(lián)研究發(fā)現(xiàn)帕金森氏癥易感基因
Science：在嚙齒類身上測(cè)試對(duì)帕金森氏病的脊髓治療
生物谷推薦原文出處：
JCB doi: 10.1083/jcb.200904103
BAG1 restores formation of functional DJ-1 L166P dimers and DJ-1 chaperone activity
Sebastian Deeg1, Mathias Gralle2, Kamila Sroka1, Mathias B?hr1,3, Fred Silvester Wouters2,3, and Pawel Kermer1,3
Mutations in the gene coding for DJ-1 protein lead to early-onset recessive forms of Parkinson’s disease. It is believed that loss of DJ-1 function is causative for disease, although the function of DJ-1 still remains a matter of controversy. We show that DJ-1 is localized in the cytosol and is associated with membranes and organelles in the form of homodimers. The disease-related mutation L166P shifts its subcellular distribution to the nucleus and decreases its ability to dimerize, impairing cell survival. Using an intracellular foldase biosensor, we found that wild-type DJ-1 possesses chaperone activity, which is abolished by the L166P mutation. We observed that this aberrant phenotype can be reversed by the expression of the cochaperone BAG1 (Bcl-2–associated athanogene 1), restoring DJ-1 subcellular distribution, dimer formation, and chaperone activity and ameliorating cell survival.
