Rethinking lysosomes and lysosomal disease

Lysosomal storage diseases were recognized and defined over a century ago as a class of disorders affecting mostly children and causing systemic disease often accompanied by major neurological consequences. Since their discovery, research focused on understanding their causes has been an important driver of our ever-expanding knowledge of cell biology and the central role that lysosomes play in cell function. Today we recognize over 50 so-called storage diseases, with most understood at the level of gene, protein and pathway involvement, but few fully clarified in terms of how the defective lysosomal function causes brain disease; even fewer have therapies that can effectively rescue brain function. Importantly, we also recognize that storage diseases are not simply a class of lysosomal disorders all by themselves, as increasingly a critical role for the greater lysosomal system with its endosomal, autophagosomal and salvage streams has also emerged in a host of neurodevelopmental and neurodegenerative diseases. Despite persistent challenges across all aspects of these complex disorders, and as reflected in this and other articles focused on lysosomal storage diseases in this special issue of Neuroscience Letters, the progress and promise to both understand and effectively treat these conditions has never been greater.