Clarifying lysosomal storage diseases

Abstract

Lysosomal storage diseases (LSDs) are a class of metabolic disorders caused by mutations in proteins critical for lysosomal function. Such proteins include lysosomal enzymes, lysosomal integral membrane proteins, and proteins involved in the post-translational modification and trafficking of lysosomal proteins. There are many recognized forms of LSDs and, although individually rare, their combined prevalence is estimated to be 1 in 8000 births. Over two-thirds of LSDs involve central nervous system (CNS) dysfunction (progressive cognitive and motor decline) and these symptoms are often the most debilitating. Although the genetic basis for these disorders is clear and the biochemistry of the proteins well understood, the cellular mechanisms by which deficiencies in these proteins disrupt neuronal viability remain ambiguous. In this review, we provide an overview of the widespread cellular perturbations occurring in LSDs, how they might be linked and interventions that may specifically or globally correct those defects.

Figure 1

Lysosomal proteins reach the lysosome directly, via the trans-Golgi network (TGN), or indirectly by way of the plasma membrane, as reviewed elsewhere [9]. In the direct pathway, upon trafficking to the TGN, some oligosaccharide side chains acquire the mannose-6-phosphate (M6P) recognition marker. Enzymes with this modification are recognized by cation-dependent and cation-independent mannose-6-phosphate receptors (M6PRs) in the TGN, mediating their sorting into the endosome-lysosome pathway [89, 90]. M6P-tagged molecules that escape M6PR recognition in the TGN are transported to the cell surface and secreted into the extracellular fluid. Secreted M6P labeled proteins are recognized by M6PR on the extracellular plasma membrane and delivered to the lysosome by receptor mediated endocytosis. This is the general mechanism underlying ERT for the soluble lysosomal hydrolase deficiencies found in several diseases (Table 1). In both direct and indirect pathways, acidification in early endosomes or lysosomes releases M6PR-hydrolase binding and the receptor is recycled back to the TGN for additional retrieval. Uptake of lysosomal hydrolases can also occur via the mannose receptor, as in the case of β-glucosidase replacement therapy for Gaucher disease.

Figure 2

General organization and function of various integral membrane proteins important for trafficking of lysosomal enzymes (e.g., LIMP2 and PS1), lysosomal function (e.g., V-ATPase, TRPML1 and LAMP-1), cholesterol homeostasis (e.g., NPC1 NPC2, and LAMP2). Malfunction of these proteins have been implicated in multiple LSDs (Table 1). It is currently unknown if PS1 remains associated with Vo as it traffics to the lysosome, but this seems a likely possibility, given its presence in autophagic vesicles.