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(huì)逐漸僵直,、肌無力，最后導(dǎo)致痙攣性癱瘓,，同時(shí)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HSP的基因變異。這為查明神經(jīng)細(xì)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,。
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》上發(fā)表文章稱，位于19號(hào)染色體上reticulon 2基因突變,，會(huì)導(dǎo)致HSP,。研究小組共確認(rèn)了3個(gè)可導(dǎo)致HSP的reticulon 2基因變異。此外他們還發(fā)現(xiàn),，該基因會(huì)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)HSP有關(guān)。
對(duì)于細(xì)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(xì)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(hào)和調(diào)控細(xì)胞內(nèi)其他成分等方面都不可或缺,。而reticulon蛋白在塑造細(xì)胞內(nèi)質(zhì)網(wǎng)方面扮演著重要角色,，reticulon 2基因則負(fù)責(zé)為reticulon蛋白進(jìn)行遺傳編碼。
大多數(shù)神經(jīng)退行性疾病都與神經(jīng)細(xì)胞軸突退化有關(guān),，一旦軸突退化,，信號(hào)則無法通過神經(jīng)細(xì)胞傳遞，從而導(dǎo)致中樞神經(jīng)系統(tǒng)信號(hào)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(xì)胞內(nèi)質(zhì)網(wǎng)的缺陷會(huì)導(dǎo)致軸突退化。
領(lǐng)導(dǎo)該項(xiàng)研究的劍橋大學(xué)埃文-里德博士指出,，新研究發(fā)現(xiàn)對(duì)于那些具有HSP家族遺傳史的家庭來說十分重要,，能提示這些家庭進(jìn)行一些相應(yīng)的遺傳咨詢和測(cè)試。而新的病理機(jī)制研究則為科學(xué)家們提供了一個(gè)平臺(tái),，使其可以進(jìn)一步研究某些神經(jīng)性疾病,，如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,Hiroyuki Ishiura, Justin Price, Alleene Strickland, Michael A. Gonzalez, Lisa Baumbach-Reardon, Tine Deconinck, Jia Huang, Giorgio Bernardi,, Jeffery M. Vance,Mark T. Rogers0, Shoji Tsuji, Peter De Jonghe, Margaret A. Pericak-Vance, Ludger Schüls,, Antonio Orlacchio,, Evan Reid and 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.
