The rapidly evolving view of lysosomal storage diseases

Abstract

Lysosomal storage diseases are a group of metabolic disorders caused by deficiencies of several components of lysosomal function. Most commonly affected are lysosomal hydrolases, which are involved in the breakdown and recycling of a variety of complex molecules and cellular structures. The understanding of lysosomal biology has progressively improved over time. Lysosomes are no longer viewed as organelles exclusively involved in catabolic pathways, but rather as highly dynamic elements of the autophagic-lysosomal pathway, involved in multiple cellular functions, including signaling, and able to adapt to environmental stimuli. This refined vision of lysosomes has substantially impacted on our understanding of the pathophysiology of lysosomal disorders. It is now clear that substrate accumulation triggers complex pathogenetic cascades that are responsible for disease pathology, such as aberrant vesicle trafficking, impairment of autophagy, dysregulation of signaling pathways, abnormalities of calcium homeostasis, and mitochondrial dysfunction. Novel technologies, in most cases based on high-throughput approaches, have significantly contributed to the characterization of lysosomal biology or lysosomal dysfunction and have the potential to facilitate diagnostic processes, and to enable the identification of new therapeutic targets.

Keywords: autophagy; lysosomal biology; lysosomal storage diseases; lysosomes.

Figure 1. The evolution of the knowledge on LSDs

After the identification of the first clinical phenotypes during of the 19th century, the knowledge on LSDs evolved following the recognition of lysosomes in 1955/56 and the demonstration of the biochemical defects underlying LSDs, starting from 1963. Between the 1970s and 1990s, research in this field was focused on the mannose‐6‐phosphate receptor pathway and on the mechanisms underlying the sorting of lysosomal enzymes, on the identification of the molecular bases of LSDs, and on the development of tools and strategies to investigate lysosomal biology. The first attempts to treat these disorders by enzyme replacement therapy started in the 1990s. Current research is now focusing on the role of lysosomes as signaling platforms controlling cellular metabolism and on the development of new therapeutic approaches.

Figure 2. New technologies to study lysosomal function and biology

New technologies, in most cases based on high‐throughput techniques combined with bioinformatic analysis, have been exploited for the diagnostic work‐up in patients with a suspected LSD, for the identification of new disease genes, for the search of disease biomarkers, for the characterization of lysosome biology and disease mechanisms, and for the identification and validation of new therapeutic targets.

Figure 3. The mechanisms involved in the pathophysiology of LSD

The accumulation of undegraded substrates triggers multiple events that are currently emerging as important players in the pathogenesis of LSDs. These events include storage of secondary substrates unrelated to the defective enzyme; abnormal composition of membranes and aberrant fusion and intracellular trafficking of vesicles; impairment of autophagy; perturbation of calcium homeostasis; and mitochondrial dysfunction and oxidative stress. In addition to the events shown in the figure, in several LSDs storage triggers dysregulation of signaling pathways and activation of inflammation.