近日,，由英國劍橋大學(xué)和美國邁阿密大學(xué)科學(xué)家領(lǐng)導(dǎo)的研究小組在最新一期《臨床調(diào)查雜志》（The Journal of Clinical Investigation）上發(fā)表文章稱,，位于19號染色體上reticulon 2基因突變,，會導(dǎo)致遺傳性痙攣性截癱(HSP),。
遺傳性痙攣性截癱(HSP)是一種較為少見的家族遺傳神經(jīng)系統(tǒng)退行性變性疾病,，病人的雙下肢會逐漸僵直,、肌無力，最后導(dǎo)致痙攣性癱瘓,，同時伴生多種并發(fā)癥,。這種疾病病因復(fù)雜，目前學(xué)界還不是很清楚,。而最近英美科學(xué)家稱,，他們研究發(fā)現(xiàn)了可導(dǎo)致某種遺傳性痙攣性截癱(HSP)的基因變異。這為查明神經(jīng)細胞退化的原因提供了重要線索,，也給神經(jīng)系統(tǒng)退行性變性疾病的治療帶來了希望,。
研究小組共確認了3個可導(dǎo)致遺傳性痙攣性截癱(HSP)的reticulon 2基因變異。此外他們還發(fā)現(xiàn),，該基因會與痙攣蛋白基因發(fā)生反應(yīng),，而這種基因變異也與大多數(shù)遺傳性痙攣性截癱(HSP)有關(guān)。
對于細胞功能的發(fā)揮來說,，內(nèi)質(zhì)網(wǎng)的作用十分重要,，這種細胞質(zhì)內(nèi)廣泛分布的三維網(wǎng)狀膜系統(tǒng)，在合成蛋白質(zhì),、轉(zhuǎn)導(dǎo)鈣信號和調(diào)控細胞內(nèi)其他成分等方面都不可或缺,。而reticulon蛋白在塑造細胞內(nèi)質(zhì)網(wǎng)方面扮演著重要角色，reticulon 2基因則負責為reticulon蛋白進行遺傳編碼,。
大多數(shù)神經(jīng)退行性疾病都與神經(jīng)細胞軸突退化有關(guān),，一旦軸突退化，信號則無法通過神經(jīng)細胞傳遞，從而導(dǎo)致中樞神經(jīng)系統(tǒng)信號傳遞的中斷,。該研究則提供了目前為止最為直接的證據(jù),，表明細胞內(nèi)質(zhì)網(wǎng)的缺陷會導(dǎo)致軸突退化。
領(lǐng)導(dǎo)該項研究的劍橋大學(xué)埃文·里德博士指出,，新研究發(fā)現(xiàn)對于那些具有遺傳性痙攣性截癱(HSP)家族遺傳史的家庭來說十分重要,，能提示這些家庭進行一些相應(yīng)的遺傳咨詢和測試。而新的病理機制研究則為科學(xué)家們提供了一個平臺,，使其可以進一步研究某些神經(jīng)性疾病,，如遺傳性痙攣性截癱(HSP)和多發(fā)性硬化癥患者的軸突受損情況，從而為這些疾病的治療帶來新希望,。（生物谷Bioon.com）
doi:10.1172/JCI60560.
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Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12
Gladys Montenegro, Adriana P. Rebelo, James Connell, Rachel Allison, Carla Babalini, Michela D’Aloia, Pasqua Montieri, Rebecca Schüle,Stephan Züchner
Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules — receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) — have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.
