Lysosomal storage disease | EPFL Graph Search

Lysosomal storage diseases (LSDs; ˌlaɪsəˈsoʊməl) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it. Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar-containing proteins), or so-called mucopolysaccharides. Individually, lysosomal storage diseases occur with incidences of less than 1:100,000; however, as a group, the incidence is about 1:5,000 – 1:10,000. Most of these disorders are autosomal recessively inherited such as Niemann–Pick disease, type C, but a few are X-linked recessively inherited, such as Fabry disease and Hunter syndrome (MPS II). The lysosome is commonly referred to as the cell's recycling center because it processes unwanted material into substances that the cell can use. Lysosomes break down this unwanted matter by enzymes, highly specialized proteins essential for survival. Lysosomal disorders are usually triggered when a particular enzyme exists in too small an amount or is missing altogether. When this happens, substances accumulate in the cell. In other words, when the lysosome does not function normally, excess products destined for breakdown and recycling are stored in the cell. Like other genetic disorders, individuals inherit lysosomal storage diseases from their parents. Although each disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic – all lysosomal disorders originate from an abnormal accumulation of substances inside the lysosome. Lysosomal storage diseases affect mostly children and they often die at a young age, many within a few months or years of birth.

Post-translational regulation of neuronal differentiation

Jaipreet Singh Loomba

Glycosphingolipids (GSLs) are amphipathic lipid moieties that make up only 3% of the total lipid content of the cell and are almost exclusively expressed at the Plasma Membrane(PM). They are key drivers of signalling hotspots known as âlipid-raftsâ as well as acting as primary signalling molecules themselves. Pathologically, perturbations in their synthesis (Knock-Out mice models) and disorders in their metabolism(Lysosomal storage disorders), both converge on neurological symptoms. In fact, during neuronal development, stem cells have been known to completely remodel their glycosphingolipid profiles, so much so, that the developmental stages of the nervous system have been associated with the expression of different glycosphingolipids. This coordinated change in the expression of glycosphingolipids has been previously attributed to the transcriptional shift in the the expression of genes encoding specific Glycosphingolipid Synthesizing Enzymes (GSEs) observed over neuronal development and, more recently, shown to be internally regulated by the GSLs themselves whereby globosides negatively regulate the expression of the ganglioside synthesizing enzyme GM3S via a neuronal transcription factor AUTS2. In this thesis I show that there exists an extra layer of post-translational regulation that is active over neuronal development that destabilizes the Gb3 synthesizing enzyme, Gb3S, on one hand while stabilizing the GM3S on the other. The regulatory mechanism achieves this effect by doubling the rate of degradation of Gb3S in neuronal cells, probably via membrane trafficking events. The exact details of the stabilization effect of GM3S remains to be determined as the results could not ascertain if it was the same mechanism or a completely different one. My study goes on to show that this regulatory mechanism is activated early during development, preceding the changes in canonical stem and neuronal markers. Morphologically, the study points towards a post-compaction but pre-cavitation (E2.5-E3.5) point of activation for the mechanism of Gb3S destabalization, relative to early mouse embryological development. Furthermore, I found that the Gb3S interactor and AUTS2 transcriptional target UCHL1 is a key regulatory unit of the machinery such that inhibiting its activity results in a specific rescue of the Gb3S enzyme.

EPFL2021

Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells[S]

Jonathan Paz Montoya, Marc Moniatte

In specialized cell types, lysosome-related organelles support regulated secretory pathways, whereas in nonspecialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol-storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Here, we report that cyclodextrin triggers the secretion of the endo/lysosomal content in nonspecialized cells and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We also find that the secretion of the endo/lysosome content occurs via a mechanism dependent on the endosomal calcium channel mucolipin-1, as well as FYCO1, the AP1 adaptor, and its partner Gadkin. We conclude that endo-lysosomes in nonspecialized cells can acquire secretory functions elicited by cyclodextrin and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.

2019

Post-translational regulation of neuronal differentiation

Jaipreet Singh Loomba

EPFL2021