2012年10月30日 訊 /生物谷BIOON/ --近日，Journal of Cell Biology雜志上刊登的一項(xiàng)研究揭示了轉(zhuǎn)錄因子STAT3是保留在神經(jīng)細(xì)胞軸突中幫助防止神經(jīng)退行性疾病,。這一發(fā)現(xiàn)可能為未來開發(fā)治療藥物以減緩神經(jīng)損傷與神經(jīng)退行性疾病鋪平了道路。
盧伽雷氏?。↙ou Gehrig's Disease）及其他神經(jīng)退行性疾病中,，神經(jīng)細(xì)胞經(jīng)常出現(xiàn)死亡，軸突日益惡化,。而最新研究證實(shí)軸突變性可能是患者一個(gè)治療轉(zhuǎn)折點(diǎn),。研究人員測(cè)試了幾種能夠保存軸突的蛋白質(zhì)。這些分子之一CNTF能在嚙齒類動(dòng)物搶救軸突,，延長(zhǎng)他們的生命,。但它在臨床試驗(yàn)中，引起嚴(yán)重的副作用。
基于以上考慮,，德國維爾茨堡大學(xué)Michael Sendtner等研究人員猜測(cè)CNTF的下游可能是一個(gè)理想作用環(huán)節(jié)來治療運(yùn)動(dòng)神經(jīng)元疾病,。
為了分析CNTF是如何工作的，Sendtner和他的同事們研究了突變小鼠,，以模仿ALS,。研究人員發(fā)現(xiàn)，CNTF不僅防止嚙齒類動(dòng)物運(yùn)動(dòng)神經(jīng)元的萎縮,，同時(shí)也減少軸突的腫脹,，軸突腫脹是變性的標(biāo)記。
據(jù)了解,，CNTF能間接開啟轉(zhuǎn)錄因子STAT3,，因此，研究人員希望確定STAT3是否是CNTF保護(hù)軸突的背后原因,。他們測(cè)試是否CNTF可以保護(hù)缺乏STAT3的運(yùn)動(dòng)神經(jīng)元,，發(fā)現(xiàn)軸突缺乏STAT3基因的小鼠給予神經(jīng)營養(yǎng)因子治療后，缺乏STAT3的軸突是對(duì)照組的一半,。
一旦STAT3被激活時(shí),，STAT3進(jìn)入神經(jīng)元細(xì)胞核內(nèi)開啟基因。但是,，研究人員驚奇地發(fā)現(xiàn)軸突STAT3并沒有移動(dòng)到細(xì)胞核內(nèi),，而在軸突外面發(fā)揮影響。具體來說,，該團(tuán)隊(duì)發(fā)現(xiàn)激活的STAT3抑制Stathmin蛋白,，Stathmin會(huì)破壞正常微管。當(dāng)從突變小鼠除去Stathmin蛋白后,，突變小鼠運(yùn)動(dòng)神經(jīng)元軸突與正常小鼠軸突以相同的速率生長(zhǎng),，突變小鼠給予CNTF后，軸突生長(zhǎng)更快快,。這些結(jié)果表明神經(jīng)營養(yǎng)因子主要抑制Stathmin蛋白,，刺激軸突生長(zhǎng)，阻止Stathmin蛋白的藥物可能減緩神經(jīng)退行性疾病患者神經(jīng)元衰退,。（生物谷：Bioon.com）
doi:10.1083/jcb.201203109
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Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease.
Bhuvaneish Thangaraj Selvaraj, Nicolas Frank, Florian L.P. Bender, Esther Asan, and Michael Sendtner.
Axonal maintenance, plasticity, and regeneration are influenced by signals from neighboring cells, in particular Schwann cells of the peripheral nervous system. Schwann cells produce neurotrophic factors, but the mechanisms by which ciliary neurotrophic factor (CNTF) and other neurotrophic molecules modify the axonal cytoskeleton are not well understood. In this paper, we show that activated signal transducer and activator of transcription-3 (STAT3), an intracellular mediator of the effects of CNTF and other neurotrophic cytokines, acts locally in axons of motoneurons to modify the tubulin cytoskeleton. Specifically, we show that activated STAT3 interacted with stathmin and inhibited its microtubule-destabilizing activity. Thus, ectopic CNTF-mediated activation of STAT3 restored axon elongation and maintenance in motoneurons from progressive motor neuronopathy mutant mice, a mouse model of motoneuron disease. This mechanism could also be relevant for other neurodegenerative diseases and provide a target for new therapies for axonal degeneration.
