Neuronal Ceroid Lipofuscinoses (NCLs), commonly known as Batten disease, constitute a group of the most prevalent neurodegenerative lysosomal storage disorders (LSDs). Mutations in at least 13 different genes (called CLNs) cause various forms of NCLs. Clinically, the NCLs manifest early impairment of vision, progressive decline in cognitive and motor functions, seizures and a shortened lifespan. At the cellular level, all NCLs show intracellular accumulation of autofluorescent material (called ceroid) and progressive neuron loss. Despite intense studies the normal physiological functions of each of the CLN genes remain poorly understood. Consequently, the development of mechanism-based therapeutic strategies remains challenging. Endolysosomal dysfunction contributes to pathogenesis of virtually all LSDs. Studies within the past decade have drastically changed the notion that the lysosomes are merely the terminal degradative organelles. The emerging new roles of the lysosome include its central role in nutrient-dependent signal transduction regulating metabolism and cellular proliferation or quiescence. In this review, we first provide a brief overview of the endolysosomal and autophagic pathways, lysosomal acidification and endosome-lysosome and autophagosome-lysosome fusions. We emphasize the importance of these processes as their dysregulation leads to pathogenesis of many LSDs including the NCLs. We also describe what is currently known about each of the 13 CLN genes and their products and how understanding the emerging new roles of the lysosome may clarify the underlying pathogenic mechanisms of the NCLs. Finally, we discuss the current and emerging therapeutic strategies for various NCLs.

中文翻译：

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溶酶体和神经元蜡样脂褐质的新作用


神经元蜡质脂褐质沉积症 (NCL)，通常称为巴顿病，是一组最常见的神经退行性溶酶体贮积症 (LSD)。至少 13 个不同基因（称为 CLN）的突变会导致各种形式的 NCL。临床上，NCL 表现为早期视力障碍、认知和运动功能进行性下降、癫痫发作和寿命缩短。在细胞水平上，所有 NCL 均显示细胞内自发荧光物质（称为蜡样质）的积累和进行性神经元损失。尽管进行了大量研究，但对每个 CLN 基因的正常生理功能仍然知之甚少。因此，基于机制的治疗策略的开发仍然具有挑战性。内溶酶体功能障碍导致几乎所有 LSD 的发病机制。过去十年的研究极大地改变了溶酶体只是最终降解细胞器的观念。溶酶体的新作用包括其在调节代谢和细胞增殖或静止的营养依赖性信号转导中的核心作用。在这篇综述中，我们首先简要概述了内溶酶体和自噬途径、溶酶体酸化以及内体-溶酶体和自噬体-溶酶体融合。我们强调这些过程的重要性，因为它们的失调会导致包括 NCL 在内的许多 LSD 的发病机制。我们还描述了目前对 13 个 CLN 基因及其产物的了解，以及了解溶酶体的新作用如何可以阐明 NCL 的潜在致病机制。最后，我们讨论了各种 NCL 的当前和新兴治疗策略。