Invertebrate models of lysosomal storage disease: what have we learned so far?

Abstract

The lysosomal storage diseases (LSDs) collectively account for death in 1 in 8,000 children. Although some forms are treatable, they are essentially incurable and usually are lethal in the first decade of life. The most intractable forms of LSD are those with neuronal involvement. In an effort to identify the pathological signaling driving pathology in the LSDs, invertebrate models have been developed. In this review, we outline our current understanding of LSDs and recent findings using invertebrate models. We outline strategies and pitfalls for the development of such models. Available models of LSD in Drosophila and Caenorhabditis elegans are uncovering roles for LSD-related proteins with previously unknown function using both gain-of-function and loss-of-function strategies. These models of LSD in Drosophila and C. elegans have identified potential pathogenic signaling cascades that are proving critical to our understanding of these lethal diseases.

Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders

“…Early phenotypes associated with spin mutants include reduced viability and morphological abnormalities at the larval neuromuscular synapses and enlarged lysosomes ( Sweeney and Davis, 2002 ). Typically, LSD are among the most common childhood neurodegenerative diseases ( Hindle et al. , 2011 ), and this is reflected in the shortened life span and reduced mobility of young spin mutant flies ( Nakano et al.…”

“…, 2009 ); as well as dnpc1 and dnpc2, critical for lipid transport and dsap-r , the pro-saposin ortholog for sphingolipid metabolism ( Hindle et al. , 2017 ), in addition to many genes involved in lysosomal storage disorders; reviewed in Hindle et al. (2011) .…”

Lipid metabolic perturbation is an early-onset phenotype in adultspinmutants: aDrosophilamodel for lysosomal storage disorders

“…Despite these differences, many mammalian genes for lipid metabolism and transport are functionally conserved in Drosophila suggesting common principles in their metabolism and transport [13]. Furthermore, many relevant human disease associated genes connected to lipid metabolism and transport are functionally conserved; these include Taz mitochondrial lipid remodeling (Barth syndrome; [14], Cerk for ceramide metabolism (Retinitis Pigmentosa; [15] as well as dnpc1 and dnpc2 for lipid transport and dsapr, the pro-saposin ortholog for sphingolipid metabolism (all lysosomal storage disorders; reviewed in [16].…”

“…Contrary to other disease models or patient samples, systematic and kinetic studies on lipids are relatively easily carried out in Drosophila, which is a wellaccepted animal model for human disease [17]. We focused on fly spinster (spin) mutants, which exhibit neurodegeneration with LSD-like features [16,[18][19][20]. Lipid metabolic changes in spin mutants have not been characterized despite their established link to neurodegeneration and their use as genetic tool to perturb sphingolipid levels [21][22][23].…”

The LUX Score: A Metric for Lipidome Homology

“…A lipidome can be an indicator of health, disease, stress or metabolic state. Using model organisms, the role of lipid metabolism has been studied in diseases such as diabetes, metabolic syndrome, neurodegeneration and cancer (Yetukuri et al, 2007;Kühnlein, 2012;Subramanian et al, 2013;Hindle et al, 2011;Lopez and Scott, 2013;Kiebish et al, 2008). To this end, lipidomes from yeast and fruitfly have been characterised (Ejsing et al, 2009;Guan et al, 2010;Carvalho et al, 2012;Klose et al, 2012;Guan et al, 2013) enabling one to identify fundamental lipid metabolic processes (Lam and Shui, 2013;Peng and Frohman, 2012).…”