Basak I, Wicky H E, McDonald K O, Xu J B, Palmer J E, Best H L, Lefrancois S, Lee S Y, Schoderboeck L, Hughes S M
Neurodegenerative and Lysosomal Disease Laboratory, Department of Biochemistry, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, 710 Cumberland Street, Dunedin, 9016, New Zealand.
School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Wales, CF10 3AX, United Kingdom.
Cell Mol Life Sci. 2021 May;78(10):4735-4763. doi: 10.1007/s00018-021-03813-x. Epub 2021 Apr 1.
Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations in thirteen CLN genes. Mutations in one CLN gene, CLN5, cause variant late-infantile NCL, with an age of onset between 4 and 7 years. The CLN5 protein is ubiquitously expressed in the majority of tissues studied and in the brain, CLN5 shows both neuronal and glial cell expression. Mutations in CLN5 are associated with the accumulation of autofluorescent storage material in lysosomes, the recycling units of the cell, in the brain and peripheral tissues. CLN5 resides in the lysosome and its function is still elusive. Initial studies suggested CLN5 was a transmembrane protein, which was later revealed to be processed into a soluble form. Multiple glycosylation sites have been reported, which may dictate its localisation and function. CLN5 interacts with several CLN proteins, and other lysosomal proteins, making it an important candidate to understand lysosomal biology. The existing knowledge on CLN5 biology stems from studies using several model organisms, including mice, sheep, cattle, dogs, social amoeba and cell cultures. Each model organism has its advantages and limitations, making it crucial to adopt a combinatorial approach, using both human cells and model organisms, to understand CLN5 pathologies and design drug therapies. In this comprehensive review, we have summarised and critiqued existing literature on CLN5 and have discussed the missing pieces of the puzzle that need to be addressed to develop an efficient therapy for CLN5 Batten disease.
神经元蜡样脂褐质沉积症（NCL），也被称为巴顿病，是一种无法治愈的儿童脑部疾病。NCL的十三种类型是由十三个CLN基因的突变引起的。一个CLN基因CLN5的突变会导致变异型晚发性婴儿NCL，发病年龄在4至7岁之间。CLN5蛋白在大多数研究的组织中普遍表达，在大脑中，CLN5在神经元和神经胶质细胞中均有表达。CLN5的突变与自荧光储存物质在溶酶体（细胞的回收单元）中在大脑和外周组织中的积累有关。CLN5存在于溶酶体中，其功能仍然不明。最初的研究表明CLN5是一种跨膜蛋白，后来发现它被加工成一种可溶性形式。已经报道了多个糖基化位点，这可能决定其定位和功能。CLN5与几种CLN蛋白以及其他溶酶体蛋白相互作用，使其成为理解溶酶体生物学的重要候选者。关于CLN5生物学的现有知识源于使用几种模式生物的研究，包括小鼠、绵羊、牛、狗、黏菌和细胞培养。每种模式生物都有其优点和局限性，因此采用组合方法，同时使用人类细胞和模式生物，对于理解CLN5病理和设计药物治疗至关重要。在这篇全面的综述中，我们总结并批判了关于CLN5的现有文献，并讨论了为开发针对CLN5巴顿病的有效疗法而需要解决的谜团中的缺失部分。
