Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 23: Lysosomal Disorders

Doug A. Brooks

Maria Fuller

Sansom Institute, University of South Australia, Molecular Medicine Sector, Adelaide, Australia

Women's and Children's Hospital, Lysosomal Diseases Research Unit, Department of Genetic Medicine, Adelaide, Australia

Lysosomal storage disorders are a group of over 50 different genetic diseases that result from lysosomal dysfunction. This disruption of lysosomal function can involve either a specific lysosomal hydrolase deficiency, a defect in lysosomal protein processing, or impaired lysosomal biogenesis. To appreciate the pathogenesis of lysosomal disorders fully, it is important to understand the dynamics of endosome–lysosome organelles, their capacity for the uptake and degradation of complex macromolecules, and how lysosomal biogenesis and hydrolysis are altered by substrate storage. The focus of this chapter will be on recognized lysosomal disorders and what is known about the composition and the function of endosome–lysosome organelles in these diseases. The lysosomal network will be discussed with a view to correlating the main site of endosome–lysosome degradation and the site of substrate accumulation in lysosomal disorders. A major unanswered question for lysosomal storage disorders is how an enzyme deficiency and the resulting storage of undegraded macromolecules impact on cells to cause organ dysfunction and disease.

A patient with possible Hurler syndrome was first described by Berkhan in 1907 [1], and it may ...