Pathogenic cascades in lysosomal disease-Why so complex? - PubMed (original) (raw)

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Pathogenic cascades in lysosomal disease-Why so complex?

S U Walkley. J Inherit Metab Dis. 2009 Apr.

Abstract

Lysosomal disease represents a large group of more than 50 clinically recognized conditions resulting from inborn errors of metabolism affecting the organelle known as the lysosome. The lysosome is an integral part of the larger endosomal/lysosomal system, and is closely allied with the ubiquitin-proteosomal and autophagosomal systems, which together comprise essential cell machinery for substrate degradation and recycling, homeostatic control, and signalling. More than two-thirds of lysosomal diseases affect the brain, with neurons appearing particularly vulnerable to lysosomal compromise and showing diverse consequences ranging from specific axonal and dendritic abnormalities to neuron death. While failure of lysosomal function characteristically leads to lysosomal storage, new studies argue that lysosomal diseases may also be appropriately viewed as 'states of deficiency' rather than simply overabundance (storage). Interference with signalling events and salvage processing normally controlled by the endosomal/lysosomal system may represent key mechanisms accounting for the inherent complexity of lysosomal disorders. Analysis of lysosomal disease pathogenesis provides a unique window through which to observe the importance of the greater lysosomal system for normal cell health.

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Figures

Figure 1

Figure 1

Schematic summarizing the concept of the lysosome as a central element in the greater lysosomal system of neurons with links to the endocytic streams from somadendritic and axonal domains, and to the macroautophagy stream and its close allies, the ubiquitin-proteosomal system (UPS) and chaperone-mediated autophagy (CMA) components. What flows into this system must also leave in some form, depicted here as the salvage pathway with delivery to the Golgi/TGN, mitochondria, and other sites in the cell. The complexity of the disease cascades in lysosomal disorders is conjectured to emanate in part from disruption of these interrelated components of the greater lysosomal system, as described in the text. (EE, early endosome; RE, recycling endosome; LE, late endosome; LY, lysosome; SE, signaling endosome; AV, autophagic vacuole; ER, endoplasmic reticulum).

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