Abstract
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.
Highlights
In 1955, Christian de Duve, while investigating the mechanism of insulin action, discovered the lysosome [1], a membrane-bound organelle which plays critical roles in the degradation and recycling of material delivered to it from both extracellular and intracellular sources [2–4]
Cellular homeostasis requires ubiquitylation, a process that facilitates specifying the proteins which are transported to the lysosomal lumen by endosomal sorting complex required for transport (ESCRT) to sort cargos tagged with ubiquitin into the invaginated endosomal membranes [11]
It has been reported that the ESCRT machinery plays an essential role in repairing injured endolysosomes and thereby providing a mechanism to protect the cells from death
Summary
In 1955, Christian de Duve, while investigating the mechanism of insulin action, discovered the lysosome [1], a membrane-bound organelle which plays critical roles in the degradation and recycling of material delivered to it from both extracellular and intracellular sources [2–4]. Lysosomal accumulation of autofluorescent material (called ceroid), increased neuronal apoptosis, dysregulated autophagy, neurodegeneration and shortened lifespan are some of the common features shared by all NCLs. Our knowledge that the lysosome functions as a nutrient sensor and the signaling hub of the cell [12–14, 53–56] may be applied to facilitate a greater understanding of the pathogenic mechanism(s) underlying the NCLs. The 13 different genes (Table 1), mutations of which cause various forms of NCLs, may be classified into four groups according to the proteins they encode.
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