Activating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti-apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia. This initially led to believe that ATF5 is not expressed in adult neurons. More recently, we reported basal neuronal ATF5 expression in adult mouse brain and its neuroprotective induction during UPR in a mouse model of status epilepticus. Here we aimed to explore whether ATF5 is also expressed by neurons in human brain both in basal conditions and in Huntington’s disease (HD), where UPR has been described to be partially impaired due to defective ATF6 processing. Apart from confirming that ATF5 is present in human adult neurons, here we report accumulation of ATF5 within the characteristic polyglutamine-containing neuronal nuclear inclusions in brains of HD patients and mice. This correlates with decreased levels of soluble ATF5 and of its antiapoptotic target MCL1. We then confirmed the deleterious effect of ATF5 deficiency in a Caenorhabditis elegans model of polyglutamine-induced toxicity. Finally, ATF5 overexpression attenuated polyglutamine-induced apoptosis in a cell model of HD. These results reflect that decreased ATF5 in HD—probably secondary to sequestration into inclusions—renders neurons more vulnerable to mutant huntingtin-induced apoptosis and that ATF5-increasing interventions might have therapeutic potential for HD.

激活转录因子5（ATF5）是在不同的细胞应激因素（如禁食，氨基酸限制，镉或亚砷酸盐）上诱导的应激反应转录因子。还诱导了ATF5，并促进抗凋亡靶基因（如MCL1）的转录，在由内质网应激触发的未折叠蛋白反应（UPR）期间。在脑中，在神经胶质瘤和神经祖细胞中发现高水平的ATF5，需要降低其ATF5水平才能分化为成熟的神经元或神经胶质。最初，这导致人们相信ATF5在成人神经元中不表达。最近，我们报道了成年癫痫持续状态小鼠模型在成年小鼠脑中基底神经元ATF5表达及其在UPR期间的神经保护诱导作用。在这里，我们旨在探讨在基础条件下和亨廷顿氏病（HD）中人脑中的神经元是否也表达了ATF5，在该疾病中，UPR被描述为由于ATF6加工缺陷而部分受损。除了确认人类成人神经元中存在ATF5之外，在这里，我们报告了HD患者和小鼠大脑中特征性的含聚谷氨酰胺的神经核内含物中ATF5的积累。这与可溶性ATF5及其抗凋亡靶标MCL1的水平降低有关。然后，我们证实了ATF5缺乏对小鼠的有害作用。秀丽隐杆线虫的多谷氨酰胺诱导的毒性模型。最后，在HD细胞模型中，ATF5过表达减弱了聚谷氨酰胺诱导的细胞凋亡。这些结果表明，HD中ATF5的降低（可能是螯合到包裹体中的继发作用）使神经元更容易受到亨廷顿基因突变诱导的细胞凋亡的影响，而增加ATF5的干预措施可能具有HD的治疗潜力。