近日,，由英國劍橋大學和美國邁阿密大學科學家領導的研究小組在最新一期《臨床調查雜志》（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,，最后導致痙攣性癱瘓，同時伴生多種并發(fā)癥,。這種疾病病因復雜,，目前學界還不是很清楚。而最近英美科學家稱,，他們研究發(fā)現了可導致某種遺傳性痙攣性截癱(HSP)的基因變異,。這為查明神經細胞退化的原因提供了重要線索，也給神經系統(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，該基因會與痙攣蛋白基因發(fā)生反應,，而這種基因變異也與大多數遺傳性痙攣性截癱(HSP)有關,。
對于細胞功能的發(fā)揮來說，內質網的作用十分重要,，這種細胞質內廣泛分布的三維網狀膜系統(tǒng),，在合成蛋白質、轉導鈣信號和調控細胞內其他成分等方面都不可或缺,。而reticulon蛋白在塑造細胞內質網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。
大多數神經退行性疾病都與神經細胞軸突退化有關,，一旦軸突退化,，信號則無法通過神經細胞傳遞，從而導致中樞神經系統(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,，表明細胞內質網的缺陷會導致軸突退化。
領導該項研究的劍橋大學埃文·里德博士指出,，新研究發(fā)現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的遺傳咨詢和測試。而新的病理機制研究則為科學家們提供了一個平臺,，使其可以進一步研究某些神經性疾病,，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.
