Pathomechanisms in the neuronal ceroid lipofuscinoses.

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.

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Copyright © 2019. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of competing interest JDC has been in receipt of research support from BioMarin Pharmaceutical Inc., Abeona Therapeutics Inc., Regenexbio Inc. and CereSpir Inc., but none of these projects relate directly to the subject of this review. The other authors have no declarations of interest.