Background:The early cellular stresses leading to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated withboth rare, early-onset familial AD (EOfAD) and common, sporadic, late-onset AD (LOAD). SORL1 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective:To investigate the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods:We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results:We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion:These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects.

中文翻译：

---

与早发性家族性阿尔茨海默病相关的分拣蛋白相关受体 1 中蛋白质截断突变的脑转录组分析表明对线粒体和核糖体功能的早期影响

背景：导致阿尔茨海默病 (AD) 的早期细胞应激仍然知之甚少，因为我们无法访问活的、无症状的人类 AD 大脑进行详细的分子分析。分拣蛋白相关受体 1 (SORL1) 编码一种多域受体蛋白，与罕见的早发性家族性 AD (EOfAD) 和常见的散发性晚发性 AD (LOAD) 遗传相关。SORL1 蛋白已显示在运输淀粉样蛋白 β A4 前体蛋白 (AβPP) 中起作用，该蛋白水解形成 AD 的病理标志之一，即淀粉样蛋白-β (Aβ) 肽。然而，对 AD 中 SORL1 的其他功能了解较少。目的：以斑马鱼为模式生物，研究SORL1中EOfAD样突变杂合性对幼年突变携带者脑转录组的影响。方法：我们进行了靶向诱变以在 SORL1 的斑马鱼直系同源物中产生类似 EOfAD 的突变，并对从野生型（非突变型）或 EOfAD 杂合型鱼类家族的兄弟姐妹的年轻成年大脑中分离的 mRNA 进行 RNA 测序——类似突变。结果：我们发现了基因表达的细微差异，表明突变鱼的线粒体和核糖体功能发生了变化。这些变化似乎与线粒体含量的变化或斑马鱼中 AβPP 相关蛋白的表达无关。结论：这些发现提供了支持 SORL1 中的 EOfAD 突变影响线粒体和核糖体功能的证据，并为未来研究阐明这些影响的性质提供了基础。