Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We show here that an altORF is nested in the FUS CDS, encoding a conserved 170 amino acid protein, altFUS. AltFUS is endogenously expressed in human tissues, notably in the motor cortex and motor neurons. Over‐expression of wild‐type FUS and/or amyotrophic lateral sclerosis‐linked FUS mutants is known to trigger toxic mechanisms in different models. These include inhibition of autophagy, loss of mitochondrial potential and accumulation of cytoplasmic aggregates. We find that altFUS, not FUS, is responsible for the inhibition of autophagy, and pivotal in mitochondrial potential loss and accumulation of cytoplasmic aggregates. Suppression of altFUS expression in a Drosophila model of FUS‐related toxicity protects against neurodegeneration. Some mutations found in ALS patients are overlooked because of their synonymous effect on the FUS protein. Yet, we show they exert a deleterious effect causing missense mutations in the overlapping altFUS protein. These findings demonstrate that FUS is a bicistronic gene and suggests that both proteins, FUS and altFUS, cooperate in toxic mechanisms.

中文翻译：

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FUS 基因是双重编码的，两种蛋白质都会导致 FUS 介导的毒性


新颖的功能编码序列（altORF）隐藏在不同阅读框架中的注释序列（CDS）中。我们在此表明​​ altORF 嵌套在 FUS CDS 中，编码保守的 170 个氨基酸蛋白 altFUS。 AltFUS 在人体组织中内源表达，特别是在运动皮层和运动神经元中。已知野生型 FUS 和/或肌萎缩侧索硬化症相关 FUS 突变体的过度表达会在不同模型中触发毒性机制。这些包括抑制自噬、线粒体电位丧失和细胞质聚集物的积累。我们发现 altFUS，而不是 FUS，负责抑制自噬，并且在线粒体电位损失和细胞质聚集体积累中起关键作用。在FUS相关毒性的果蝇模型中抑制 altFUS 表达可防止神经变性。 ALS 患者中发现的一些突变因其对 FUS 蛋白的同义作用而被忽视。然而，我们发现它们会产生有害作用，导致重叠的 altFUS 蛋白发生错义突变。这些发现表明FUS是一个双顺反子基因，并表明 FUS 和 altFUS 这两种蛋白质在毒性机制中协同作用。