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Pathogenic cascades in lysosomal disease—Why so complex?

  • SSIEM Symposium 2008
  • Published:
Journal of Inherited Metabolic Disease

Summary

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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Abbreviations

AMPA:

α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid

CMA:

chaperone-mediated autophagy

E/L:

endosomal/lysosomal

ER:

endoplasmic reticulum

GAG:

glycosaminoglycan

GSL:

glycosphingolipid

ML:

mucolipidosis

MPS:

mucopolysaccharidosis

NMDA:

N-methyl-d-aspartate

TGN:

trans-Golgi network

UPS:

ubiquitin–proteosomal system

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Acknowledgements

This work was supported by grants from the NIH (HD045561 and NS053677), the Ara Parseghian Medical Research Foundation and Dana’s Angel’s Research Trust.

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Authors and Affiliations

  1. Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY, 10461, USA

    S. U. Walkley

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  1. S. U. Walkley
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Correspondence to S. U. Walkley.

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Communicating editor: Gregory McCarthy Pastores

Competing interests: None declared

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Walkley, S.U. Pathogenic cascades in lysosomal disease—Why so complex?. J Inherit Metab Dis 32, 181–189 (2009). https://doi.org/10.1007/s10545-008-1040-5

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