Department of Biology, Trent University, Life & Health Sciences Building, 1600 West Bank Drive, Peterborough, Ontario K9L 0G2, Canada.
Dis Model Mech. 2021 Dec 1;14(12). doi: 10.1242/dmm.049152. Epub 2021 Dec 6.
The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.
神经元蜡样脂褐质沉积症（NCLs），统称为婴儿黑矇性痴呆，是一组影响全球所有年龄段和种族的神经退行性疾病。NCL 有 13 种不同的亚型，每种亚型都是由不同基因的突变引起的。NCL 的特征是各种细胞类型中不可消化的脂质和蛋白质的积累。这导致进行性神经退行性变和临床症状，包括视力丧失、进行性运动和认知能力下降、癫痫发作和过早死亡。这些疾病通常以溶酶体缺陷为特征，导致不可消化物质的积累，但对 NCL 的进一步研究表明，异常的蛋白质分泌也可能起重要作用。这一点在包括盘基网柄菌、小鼠和绵羊在内的生物医学模式生物中的最新研究工作中得到了加强。在盘基网柄菌中的研究报告了一些 NCL 相关蛋白的细胞外定位，以及 NCL 相关基因缺失对单细胞生长和多细胞发育过程中蛋白质分泌的影响。在 NCL 的哺乳动物模型中也观察到了异常的蛋白质分泌，这使得可以对患者来源的脑脊液和尿液进行检查，以寻找潜在的诊断和预后生物标志物。越来越多的证据将 13 种已知的 NCL 相关基因中的 7 种与蛋白质分泌联系起来，这表明异常分泌是多种 NCL 亚型的共同特征。这篇综述强调了蛋白质分泌异常在 NCL 中的影响，确定了潜在的感兴趣的生物标志物，并表明该领域的未来工作可以提供新的治疗见解。
