Hexanucleotide repeat expansions within the gene C9ORF72 are the most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This disease-causing expansion leads to a reduction in C9ORF72 expression levels in patients, suggesting loss of C9ORF72 function could contribute to disease. To further understand the consequences of C9ORF72 deficiency in vivo, we generated a c9orf72 mutant zebrafish line. Analysis of the adult female spinal cords revealed no appreciable neurodegenerative pathology such as loss of motor neurons or increased levels of neuroinflammation. However, detailed examination of adult female c9orf72^–/– retinas showed prominent neurodegenerative features, including a decrease in retinal thickness, gliosis, and an overall reduction in neurons of all subtypes. Analysis of rod and cone cells within the photoreceptor layer showed a disturbance in their outer segment structure and rhodopsin mislocalization from rod outer segments to their cell bodies and synaptic terminals. Thus, C9ORF72 may play a previously unappreciated role in retinal homeostasis and suggests C9ORF72 deficiency can induce tissue specific neuronal loss.

C9ORF72基因内的六核苷酸重复扩增是神经退行性疾病肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的最常见原因。这种引起疾病的扩增导致患者中 C9ORF72 表达水平降低，表明 C9ORF72 功能的丧失可能导致疾病。为了进一步了解体内 C9ORF72 缺陷的后果，我们生成了c9orf72突变斑马鱼系。对成年女性脊髓的分析显示，没有明显的神经退行性病理学，例如运动神经元的丧失或神经炎症水平的增加。然而，对成年女性c9orf72 ^–/–视网膜的详细检查显示出显着的神经退行性特征，包括视网膜厚度减少、神经胶质增生以及所有亚型神经元的总体减少。对感光层内视杆细胞和视锥细胞的分析表明，其外节结构受到干扰，视紫红质从视杆外节到细胞体和突触末端的定位错误。因此，C9ORF72 可能在视网膜稳态中发挥着以前未被认识到的作用，并表明 C9ORF72 缺陷可诱导组织特异性神经元损失。