Abstract：
Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small-alpha helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterised the phenotypes induced by a genetic loss of function (LoF) and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human WT Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterised by Lamin B2 mis-localisation. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS+/-FTD patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.
摘要：
膜联蛋白A11突变是肌萎缩侧索硬化症（ALS）的罕见原因，其中复制的蛋白质变体P36R，G38R,D40G和D40Y位于长的小α螺旋中，无序的N端。为了阐明疾病机制，我们表征了由遗传功能丧失（LoF）和体内G38R和D40G的错误表达诱导的表型。膜联蛋白A11的缺失导致斑马鱼纯合敲除幼虫的低渗透行为表型和异常轴突形态，由人类WT膜联蛋白A11拯救。膜联蛋白A11敲除/降低和ALS变体均引发以LaminB2错误定位为特征的核功能障碍。LaminB2信号也出现在前角，来自具有G38R和D40G蛋白变体的死后ALS+/-FTD患者组织的脊髓神经元。这些发现表明，突变膜联蛋白A11作为显性阴性，在动物模型中揭示了一种潜在的早期核病，突出了核包膜异常之前的行为异常。
