National Institute for Health and Welfare (THL), Public Health Genomics Unit, Helsinki, Finland.
Hum Mutat. 2010 Mar;31(3):356-65. doi: 10.1002/humu.21195.
Neuronal ceroid lipofuscinoses (NCLs) represent a group of children's inherited neurodegenerative disorders caused by mutations in at least eight different genes. Mutations in the CLN5 gene result in the Finnish variant late infantile NCL characterized by gradual loss of vision, epileptic seizures, and mental deterioration. The CLN5 gene encodes a lysosomal glycoprotein of unidentified function. In this study, we have used both transient and stable expression systems for the characterization of CLN5, focusing on the localization, processing, and intracellular trafficking. We show that CLN5 is proteolytically cleaved, and that the mature polypeptide is transported to the lysosomes. Our data provide the first evidence that soluble CLN5 protein can also undergo mannose-6-phosphate receptor-independent trafficking to the lysosomes. We studied the localization and maturation of the CLN5 carrying the previously uncharacterized vLINCL disease causing mutations in HeLa cells. All analyzed disease mutations disturb the lysosomal trafficking of the mutated CLN5 proteins. The level of lysosomal targeting does not correlate, however, to disease onset, indicating that CLN5 may also function outside lysosomes. This study furthers our understanding of the basic properties of the CLN5 protein, necessary for the characterization of the consequences of disease mutations and for the planning of future therapies for vLINCL.
神经元蜡样脂褐质沉积症（NCLs）是一组由至少 8 种不同基因突变引起的儿童遗传性神经退行性疾病。CLN5 基因突变导致芬兰型晚发性婴儿 NCL，其特征是视力逐渐丧失、癫痫发作和智力恶化。CLN5 基因编码一种功能未知的溶酶体糖蛋白。在这项研究中，我们使用了瞬时和稳定表达系统来对 CLN5 进行了特征分析，重点是定位、加工和细胞内运输。我们表明 CLN5 被蛋白水解切割，成熟的多肽被运送到溶酶体。我们的数据首次提供了证据，证明可溶性 CLN5 蛋白也可以通过甘露糖-6-磷酸受体非依赖性途径转运到溶酶体。我们在 HeLa 细胞中研究了携带以前未表征的 vLINCL 疾病突变的 CLN5 的定位和成熟。所有分析的疾病突变都干扰了突变 CLN5 蛋白的溶酶体运输。然而，溶酶体靶向水平与疾病发作无关，表明 CLN5 也可能在溶酶体之外发挥作用。这项研究进一步了解了 CLN5 蛋白的基本特性，这对于表征疾病突变的后果和为 vLINCL 规划未来的治疗方法是必要的。
