Clarifying lysosomal storage diseases

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.

Introduction

In all cells, including neurons, the primary degradative organelle is the lysosome (see Glossary). Lysosomes receive their ‘substrates’ through various pathways, including endocytosis, phagocytosis and autophagy. Substrates are degraded via a finely orchestrated network of membrane-bound lysosomal proteins, soluble lysosomal hydrolases, lysosomal related organelles and other cellular constituents. When lysosomal function is impaired, neuronal dysfunction and neurodegeneration can occur. Beginning with Gaucher disease during the mid-1960s, the genetic and biochemical basis for many lysosomal storage diseases (LSDs) has been unraveled, and most have central nervous system (CNS) involvement (Table 1 and Table S1 in the supplementary material online).

All LSDs are recessively inherited monogenic disorders, of which two are X-linked. Loss-of-function mutations in one of the more than 50 known soluble enzymes (Table 1), including proteases, lipases, sulfatases, or proteins important in their synthesis or trafficking, cause substrate accumulation and lysosomal storage. Although individuals with LSD can display early symptoms, many are clinically normal at birth. This suggests that lysosomal dysfunction per se does not impact significantly the complex events of early brain development (neural induction, establishment of axis, neuronal differentiation and migration, and synapse formation). Furthermore, in the case of many different LSDs, children typically meet early developmental milestones, signifying that lysosomal storage does not affect neuronal function and maturation at early developmental stages.

Defects in proteins involved in lysosome regulation or function induce the accumulation of undigested molecules that can subsequently alter many cellular processes. These include lysosomal pH regulation, synaptic release, endocytosis, vesicle maturation, autophagy, exocytosis and Ca²⁺ homeostasis 1, 2, 3, 4. Many of these phenotypes, some of which are discussed in detail below, can be markedly improved by substrate reduction therapy (SRT), or enzyme or gene replacement (Box 1). In animal models or in patient biopsies, efficacy can be monitored by concomitant resolution of storage material 5, 6. However, such treatments are not yet available or feasible for most LSDs. Thus, understanding how the affected cellular pathways interconnect and impact the viability of neural cells is critical for future therapeutic development. A recently described transcriptional network, which controls the expression of many proteins involved in these various pathways, provides an important clue to the extent of their inter-relatedness [7]. This important discovery gives a fresh opportunity to revisit how mutations in a single gene required for lysosomal function might impact secondary cellular functions beyond the lysosome.