Abstract
Lysosomal storage diseases (LSDs) are a family of 70 metabolic disorders characterized by mutations in lysosomal proteins that lead to storage material accumulation, multiple-organ pathologies that often involve neurodegeneration, and early mortality in a significant number of patients. Along with the necessity for more effective therapies, there exists an unmet need for further understanding of disease etiology, which could uncover novel pathways and drug targets. Over the past few decades, the growth in knowledge of disease-associated pathways has been facilitated by studies in model organisms, as advancements in mutagenesis techniques markedly improved the efficiency of model generation in mammalian and non-mammalian systems. In this review we highlight non-mammalian models of LSDs, focusing specifically on the zebrafish, a vertebrate model organism that shares remarkable genetic and metabolic similarities with mammals while also conferring unique advantages such as optical transparency and amenability toward high-throughput applications. We examine published zebrafish LSD models and their reported phenotypes, address organism-specific advantages and limitations, and discuss recent technological innovations that could provide potential solutions.
Highlights
Lysosomal storage diseases (LSDs) are a family of 70 metabolic disorders caused by mutations in lysosomal proteins that lead to lysosomal dysfunction (Platt et al, 2018)
The rise in TALEN and CRISPR-Cas9 models over the past 3 years is a reflection of the recent successful implementation of these gene editing methods in the zebrafish
Disruptions in major signaling pathways were observed across several zebrafish models, and pharmacological modulations of some of these pathways resulted in rescue of LSD pathology
Summary
Lysosomal storage diseases (LSDs) are a family of 70 metabolic disorders caused by mutations in lysosomal proteins that lead to lysosomal dysfunction (Platt et al, 2018). Organization of the reported models by method of generation and year revealed a relatively large number of transient knockdowns MOs up to 2016, which gradually shifted toward stable TALEN and CRISPR-Cas models from 2017 to 2019 (Figure 1C) This occurrence is a likely reflection of the successful implementation of these gene editing methods in the zebrafish starting from 2011 (Sander et al, 2011; Hwang et al, 2013a,b, 2014; Gagnon et al, 2014). The 12 sphingolipid-associated LSDs are illustrated, and those with published zebrafish models are boxed Of these models, nine are MO knockdowns, three are generated by CRISPR-Cas, one is generated by TALENs, and one derives from the Zebrafish Mutation Project (Kettleborough et al, 2013), which used the chemical mutagen N-ENU in its forward genetics phase (Figure 2, Table 2, and Supplementary Table S1). Mucolipidosis II α/β (I-cell disease); mucolipidosis III α/β (pseudo-Hurler polydystrophy)
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