Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetically heterogeneous neurologic disorder clinically characterized by focal seizures with auditory symptoms and/or aphasia. About 20% of ADLTE families segregate disease-causing heterozygous mutations in RELN, a brain-expressed gene encoding the secreted protein Reelin. Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway. Confocal immunofluorescence analysis of transiently transfected cells shows that Reelin mutant proteins are degraded by the autophagy system, as revealed by increased formation of autophagosomes immunoreacting with the autophagy markers p62 and LC3. In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression. Finally, we show that the secretion defect of mutant proteins can be partially rescued by small-molecule correctors. Altogether, these results suggest that Reelin mutant proteins are not properly secreted and that they are degraded through the autophagy pathway.

中文翻译：

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引起癫痫的 Reelin 突变导致突变蛋白的分泌受损和细胞内降解

常染色体显性遗传性侧颞叶癫痫 (ADLTE) 是一种遗传异质性神经系统疾病，临床特征为局灶性癫痫发作伴听觉症状和/或失语。大约 20% 的 ADLTE 家族在 RELN 中分离出引起疾病的杂合突变，RELN 是一种编码分泌蛋白 Reelin 的大脑表达基因。使用基于细胞的分泌测定，我们表明致病性 RELN 突变消除或显着减少突变蛋白的分泌，并且这种分泌缺陷是由于沿分泌途径的突变 Reelin 运输受损所致。瞬时转染细胞的共聚焦免疫荧光分析表明，Reelin 突变蛋白被自噬系统降解，如与自噬标志物 p62 和 LC3 免疫反应的自噬体形成增加所揭示的那样。此外，LC3 免疫印迹显示由于突变体过表达导致自噬通量显着增加。最后，我们表明突变蛋白的分泌缺陷可以通过小分子校正剂部分挽救。总之，这些结果表明 Reelin 突变蛋白没有正确分泌，它们通过自噬途径被降解。