Lysosomal Biogenesis and Disease

This chapter introduces key concepts in the area of lysosomal biogenesis, which were initially derived from the study of lysosomal storage disorders, but more recently developed from molecular studies on vesicular traffic and the cell biology of specific endosomal–lysosomal proteins. The dynamics of the endomembrane system is discussed and includes the concepts of biosynthesis, vesicular traffic, protein processing, secretion, enzyme uptake, and the degradation of macromolecular substrates to their constituents in the endosome–lysosome network. Each section highlights potential areas of dysfunction in endosome–lysosome proteins or their processing/transport machinery, and relates this to known disease states, to both enhance discussion of key areas of lysosomal biogenesis and introduce the other chapters of this book. We hypothesise that a defect at any point in the processes of endosome–lysosome biogenesis and function is susceptible to the effects of mutation and can therefore result in a genetic disease. Even for defects in the same gene, different mutations may have dramatically different effects based on how the message and gene product interact with the processing machinery and organelle milieu. In most cases mutations will have direct and obvious functional and clinical significance, but for other defects the effects may be more subtle with either only long-term significance or obvious effects at particular stages of development. Thus, an error in protein processing or vesicular traffic may be just as important to lysosomal function as a mutation in the coding sequence of a degradive lysosomal hydrolase, as iterated in this book.