Caenorhabditis elegans as a model for lysosomal storage disorders

Voer, Gert de; Peters, Dorien J.M.; Taschner, Peter E.M.

doi:10.1016/j.bbadis.2008.04.003

Cited by 42 publications

(31 citation statements)

References 85 publications

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“…In agreement with published data (13,15,43,44), we found orthologs of both BLOC-3 subunits in vertebrates and insects but failed to detect them in nematodes. In addition, we detected orthologs of both HPS1 and HPS4 in D. discoideum, and of HPS1 in T. vaginalis (Tables S13 and S14).…”

Section: Bloc-3supporting

confidence: 82%

“…In agreement with the previous reports (13,15,39,40), we failed to detect orthologs of HPS6 outside vertebrates but found orthologs of HPS3 and HPS5 in insects and of HPS5 in nematodes. In addition, we found clearly recognizable orthologs of both HPS3 and HPS5 in D. discoideum (Tables S10 and S11).…”

Section: Bloc-2supporting

confidence: 80%

“…It was even proposed that the BLOCs were unique to vertebrates (12). However, readily recognizable orthologs of most BLOC subunits could be found in the genome of D. melanogaster (13,14), and a few BLOC subunit homologs were found in C. elegans (15). Although the function of most invertebrate counterparts of BLOC subunits has not yet been investigated, satisfyingly the fly counterparts of HPS5 and BLOS1 were shown to be required for normal biogenesis of eye pigment granules, which as noted above are considered LROs (13,14,16).…”

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confidence: 99%

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Early Origin of Genes Encoding Subunits of Biogenesis of Lysosome-related Organelles Complex-1, -2 and -3

Cheli¹,

Dell’Angelica²

2010

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Biogenesis of lysosome-related organelles complex (BLOC)-1, -2 and -3 are three multi-subunit protein complexes that are deficient in various forms of HermanskyPudlak syndrome, a human disease characterized by abnormal formation of lysosome-related organelles. Contrasting views have arisen on the evolutionary origin of these protein complexes. One view is that the BLOCs represent a recent evolutionary 'acquisition' unique to metazoans. However, the yeast proteins Mon1, Ccz1 and She3 have been reported to display homology to the HPS1 and HPS4 subunits of BLOC-3 and the BLOS2 subunit of BLOC-1, respectively. In this work, we have systematically searched for orthologs of BLOC subunits in the annotated genomes of over 160 species of eukaryotes, including metazoans and fungi in the Opisthokonta group as well as highly divergent organisms. We have found orthologs of six of the eight BLOC-1 subunits, two of the three BLOC-2 subunits, and the two BLOC-3 subunits, in some nonopisthokonts such as Dictyostelium discoideum, suggesting an early evolutionary origin for these complexes. On the other hand, we have obtained no evidence in support of the notion that yeast She3 would be an ortholog of BLOS2, and found that yeast Mon1 and Ccz1, despite displaying restricted homology to portions of HPS1 and HPS4, are unlikely to represent the orthologs of these BLOC-3 subunits. Potential orthologs of Mon1 and Ccz1 were found in humans and several other eukaryotes.

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Section: Bloc-3supporting

confidence: 82%

Section: Bloc-2supporting

confidence: 80%

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confidence: 99%

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Early Origin of Genes Encoding Subunits of Biogenesis of Lysosome-related Organelles Complex-1, -2 and -3

Cheli¹,

Dell’Angelica²

2010

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“…Nearly all of the subunits of the BLOC-1 and BLOC-2 complexes are conserved in Drosophila, where at least one subunit is glo-3 and Gut Granule Biogenesisnecessary for the biogenesis of a LRO (Falcon-Perez et al 2007;Syrzycka et al 2007). Notably, few BLOC-1 or BLOC-2 subunits are obviously conserved in C. elegans (De Voer et al 2008).…”

Section: ) Had Similar Localizations and Morphologies Inmentioning

confidence: 99%

glo-3, a Novel Caenorhabditis elegans Gene, Is Required for Lysosome-Related Organelle Biogenesis

Rabbitts¹,

Ciotti

Miller

et al. 2008

Genetics

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Gut granules are specialized lysosome-related organelles that act as sites of fat storage in Caenorhabditis elegans intestinal cells. We identified mutations in a gene, glo-3, that functions in the formation of embryonic gut granules. Some glo-3(À) alleles displayed a complete loss of embryonic gut granules, while other glo-3(À) alleles had reduced numbers of gut granules. A subset of glo-3 alleles led to mislocalization of gut granule contents into the intestinal lumen, consistent with a defect in intracellular trafficking. glo-3(À) embryos lacking gut granules developed into adults containing gut granules, indicating that glo-3(1) function may be differentially required during development. We find that glo-3(1) acts in parallel with or downstream of the AP-3 complex and the PGP-2 ABC transporter in gut granule biogenesis. glo-3 encodes a predicted membrane-associated protein that lacks obvious sequence homologs outside of nematodes. glo-3 expression initiates in embryonic intestinal precursors and persists almost exclusively in intestinal cells through adulthood. GLO-3TGFP localizes to the gut granule membrane, suggesting it could play a direct role in the trafficking events at the gut granule. smg-1(À) suppression of glo-3(À) nonsense alleles indicates that the C-terminal half of GLO-3, predicted to be present in the cytoplasm, is not necessary for gut granule formation. Our studies identify GLO-3 as a novel player in the formation of lysosome-related organelles.

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“…One approach to understanding LSDs and their pathogenic mechanisms is to focus on conserved disease genes within genetically tractable model systems. Work on conserved LSD loci has been undertaken in Drosophila and Caenorhabditis elegans with what appears to be surprisingly informative results (see also de Voer et al 2008). This review summarises the benefits, limitations and pitfalls of this approach and outlines the key findings on LSDs generated by work in invertebrate model organisms.…”

Section: Introductionmentioning

confidence: 94%

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

2011

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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.

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Caenorhabditis elegans as a model for lysosomal storage disorders

Cited by 42 publications

References 85 publications

Early Origin of Genes Encoding Subunits of Biogenesis of Lysosome-related Organelles Complex-1, -2 and -3

Early Origin of Genes Encoding Subunits of Biogenesis of Lysosome-related Organelles Complex-1, -2 and -3

glo-3, a Novel Caenorhabditis elegans Gene, Is Required for Lysosome-Related Organelle Biogenesis

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

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