The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders (LSDs), traditionally grouped together based on shared clinical symptoms. The recent emergence of new forms of NCL along with an improved understanding of endo-lysosomal system function have necessitated the reassessment of their classification and pathogenesis. Novel clinical findings, as well as observations in various animal models of NCL, have revealed significant pathological changes in regions outside the brain, as well as progression of disease along connected anatomical pathways. The characterization of animal models of NCLs has not only highlighted the vulnerability of certain neuron populations but has also revealed glial cells to be adversely affected and actively contribute to disease progression. While the lysosome has been thought of as being the ‘waste-disposal’ unit of the cell, recent evidence of the endo-lysosomal system playing a crucial role in nutrient sensing and cellular homeostasis have shown that NCL mutations have far-ranging effects on cellular functions including autophagy and synaptic dysfunction. The discovery of the machinery controlling endo-lysosomal function via transcription factor EB (TFEB) and mTORC1, have also shed light on potential mechanisms by which NCL mutations may exert their effect. While the NCLs share many common down-stream pathologies, there is a growing body of evidence for unique pathogenic pathways in each form. In light of the rapid advances in therapeutic strategies for the NCLs and LSDs, these new lessons learnt about unique NCL pathomechanisms will be key for informing the targeting, timing and strategies for future treatments.

神经元类固醇脂褐藻糖糖（NCL）是一组遗传性神经退行性溶酶体贮积病（LSD），传统上根据共同的临床症状将其分组。最近的NCL的新形式的出现与更好地理解沿内-溶酶体系统功能需要重新评估其分类和发病机理。新的临床发现以及在NCL的各种动物模型中的观察结果均揭示了大脑外部区域的重大病理变化，以及沿着相连解剖路径的疾病进展。NCLs动物模型的特征不仅突出了某些神经元种群的脆弱性，而且还揭示了神经胶质细胞受到不利影响并积极促进疾病进展。虽然溶酶体已被看作是细胞的“垃圾处理”单元，最近的证据内-溶酶体系统在营养物感应和细胞体内平衡中起着至关重要的作用，已表明NCL突变对包括自噬和突触功能障碍在内的细胞功能具有广泛的影响。通过转录因子EB（TFEB）和mTORC1控制内溶酶体功能的机制的发现，也揭示了NCL突变可能发挥其作用的潜在机制。尽管NCL共有许多常见的下游病理，但越来越多的证据表明每种形式都有独特的致病途径。鉴于NCL和LSD的治疗策略迅速发展，这些有关独特的NCL发病机制的新经验教训将成为告知未来治疗目标，时机和策略的关键。