Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease).
Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease).
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CLN3疾病模型（Batten疾病）中的神经变性和癫痫。
DOI：
10.1371/journal.pone.0157365
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Russell C
中科院分区：
文献类型：
--
作者：
Wager K;Zdebik AA;Fu S;Cooper JD;Harvey RJ;Russell C
神经元蜡样质脂褐质沉积症是一组溶酶体贮积症，包括最常见的、遗传异质性的、致命的儿童神经退行性疾病。其特征是儿童期发病、视力障碍、癫痫发作、精神运动性迟缓和痴呆。 CLN3 病，也称为 Batten 病，是由 CLN3 基因的常染色体隐性突变引起的，其中 80-85% 是约 1 kb 的缺失。目前尚无治疗方法，在经历了许多痛苦之后，这种疾病不可避免地导致过早死亡。本研究的目的是使用反义吗啉注射液生成 CLN3 疾病的斑马鱼模型，并表征 Cln3 缺陷的病理和功能后果，从而为未来的药物发现提供工具。该模型忠实地再现了 CLN3 疾病的病理体征，包括存活率降低、神经元缺失、视网膜病变、轴突病变、运动功能丧失、线粒体 ATP 合酶 c 亚基溶酶体储存和癫痫发作，尽管比人类疾病发病更早且进展更快。我们的研究提供了原理证明，证明斑马鱼相对于其他模型系统的优势可用于进一步了解 CLN3 疾病的发病机制并加速药物发现。
The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80–85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery.