Juvenile neuronal ceroid lipofuscinosis (or Batten disease) is an autosomal recessive, rare neurodegenerative disorder that affects mainly children above the age of 5 yr and is most commonly caused by mutations in the highly conserved CLN3 gene. Here, we generated cln3 morphants and stable mutant lines in zebrafish. Although neither morphant nor mutant cln3 larvae showed any obvious developmental or morphological defects, behavioral phenotyping of the mutant larvae revealed hyposensitivity to abrupt light changes and hypersensitivity to pro-convulsive drugs. Importantly, in-depth metabolomics and lipidomics analyses revealed significant accumulation of several glycerophosphodiesters (GPDs) and cholesteryl esters, and a global decrease in bis(monoacylglycero)phosphate species, two of which (GPDs and bis(monoacylglycero)phosphates) were previously proposed as potential biomarkers for CLN3 disease based on independent studies in other organisms. We could also demonstrate GPD accumulation in human-induced pluripotent stem cell-derived cerebral organoids carrying a pathogenic variant for CLN3 Our models revealed that GPDs accumulate at very early stages of life in the absence of functional CLN3 and highlight glycerophosphoinositol and BMP as promising biomarker candidates for pre-symptomatic CLN3 disease.

中文翻译：

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CLN3 缺乏会导致早期发育过程中的神经和代谢紊乱。

青少年神经元蜡质脂褐质沉着症（或 Batten 病）是一种常染色体隐性遗传、罕见的神经退行性疾病，主要影响 5 岁以上的儿童，最常见的是由高度保守的CLN3基因突变引起。在这里，我们在斑马鱼中产生了cln3 morphant 和稳定的突变体系。尽管morphant和突变cln3幼虫均未表现出任何明显的发育或形态缺陷，但突变幼虫的行为表型显示对突然的光变化不敏感，对促惊厥药物过敏。重要的是，深入的代谢组学和脂质组学分析揭示了几种甘油磷酸二酯（GPD）和胆固醇酯的显着积累，以及双（单酰基甘油）磷酸酯的整体减少，其中两种（GPD和双（单酰基甘油）磷酸酯）先前被提议为基于其他生物体的独立研究，CLN3疾病的潜在生物标志物。我们还可以证明 GPD 在携带CLN3致病性变异的人诱导多能干细胞衍生的大脑类器官中积累。我们的模型显示，在缺乏功能性 CLN3 的情况下，GPD 在生命的早期阶段积累，并强调甘油磷酸肌醇和 BMP 作为有前途的生物标志物候选者用于出现症状前的CLN3疾病。