Exacerbating and reversing lysosomal storage diseases: from yeast to humans

Lysosomal storage diseases (LSDs) arise from monogenic deficiencies in lysosomal proteins and pathways and are characterized by a tissue-wide accumulation of a vast variety of macromolecules, normally specific to each genetic lesion. Strategies for treatment of LSDs commonly depend on reduction of the offending metabolite(s) by substrate depletion or enzyme replacement. However, at least 44 of the ~50 LSDs are currently recalcitrant to intervention. Murine models have provided significant insights into our understanding of many LSD mechanisms; however, these systems do not readily permit phenotypic screening of compound libraries, or the establish-ment of genetic or gene-environment interaction networks. Many of the genes causing LSDs are evolutionarily conserved, thus facilitating the application of models system to provide additional insight into LSDs. Here, we review the utility of yeast models of 3 LSDs: Batten disease, cystinosis, and Niemann-Pick type C disease. We will focus on the translation of research from yeast models into human patients suffering from these LSDs. We will also discuss the use of yeast models to investigate the penetrance of LSDs, such as Niemann-Pick type C disease, into more prevalent syndromes including viral infection and obesity

Evidence for co-evolutionary history of early diverging Lycopodiaceae plants with fungi

Lycopods are tracheophytes in the Kingdom Plantae and represent one of the oldest lineages of living vascular plants. Symbiotic interactions between these plants with fungi and bacteria, including fine root endophytes in Endogonales, have been hypothesized to have helped early diverging plant lineages colonize land. However, attempts to study the lycopod rhizobiome in its natural environment are still limited. In this study, we used Illumina amplicon sequencing to characterize fungal and bacterial diversity in nine Lycopodiaceae (club moss) species collected in New Zealand. This was done with generic fungal ITS rDNA primers, as well as Endogonales- and arbuscular mycorrhizal fungi (AMF)-selective primer sets targeting the 18S rDNA, and generic bacterial primers targeting the V4 region of the 16S rDNA. We found that the Lycopodiaceae rhizobiome was comprised of an unexpected high frequency of Basidiomycota and Ascomycota coincident with a low abundance of Endogonales and Glomerales. The distribution and abundance of Endogonales varied with host lycopod, and included a novel taxon as well as a single operational taxonomic unit (OTU) that was detected across all plant species. The Lycopodiaceae species with the greatest number and also most unique OTUs was Phlegmariurus varius, while the plant species that shared the most fungal OTUs were Lycopodiella fastigiatum and Lycopodium scariosum. The bacterial OTU distribution was generally not consistent with fungal OTU distribution. For example, community dissimilarity analysis revealed strong concordance between the evolutionary histories of host plants with the fungal community but not with the bacterial community, indicating that Lycopodiaceae have evolved specific relationships with their fungal symbionts. Notably, nearly 16% of the ITS rDNA fungal diversity detected in the Lycopodiaceae rhizobiome remained poorly classified, indicating there is much plant-associated fungal diversity left to describe in New Zealand

Identification and Bioactivity of 3-<i>epi</i>-Xestoaminol C Isolated from the New Zealand Brown Alga <i>Xiphophora chondrophylla</i>

We report here the bioassay-guided isolation of a new 1-deoxysphingoid, 3-<i>epi</i>-xestoaminol C (<b>1</b>), isolated from the New Zealand brown alga <i>Xiphophora chondrophylla</i>. This is the first report of a 1-deoxysphingoid from a brown alga. We describe the isolation and full structure elucidation of this compound, including its absolute configuration, along with its bioactivity against mycobacteria and mammalian cell lines and preliminary mechanism of action studies using yeast chemical genomics

Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae

Eukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic backgrounds. Statin response was probed with five queries against four genetic backgrounds. The 20 resultant GINs representing drug-gene and gene-gene interactions were not conserved by functional enrichment, hierarchical clustering, and topology-based community partitioning. An unfolded protein response (UPR) community exhibited genetic background variation including different betweenness genes that were network bottlenecks, and we experimentally validated this UPR community via measurements of the UPR that were differentially activated and regulated in statin-resistant strains relative to the statin-sensitive S288C background. These network analyses by topology and function provide insight into the complexity of drug response influenced by genetic background.status: publishe

Bioactivity-Guided Metabolite Profiling of Feijoa (<i>Acca sellowiana</i>) Cultivars Identifies 4‑Cyclopentene-1,3-dione as a Potent Antifungal Inhibitor of Chitin Synthesis

Pathogenic fungi continue to develop resistance against current antifungal drugs. To explore the potential of agricultural waste products as a source of novel antifungal compounds, we obtained an unbiased GC-MS profile of 151 compounds from 16 commercial and experimental cultivars of feijoa peels. Multivariate analysis correlated 93% of the compound profiles with antifungal bioactivities. Of the 18 compounds that significantly correlated with antifungal activity, 5 had not previously been described from feijoa. Two novel cultivars were the most bioactive, and the compound 4-cyclopentene-1,3-dione, detected in these cultivars, was potently antifungal (IC₅₀ = 1–2 μM) against human-pathogenic <i>Candida</i> species. Haploinsufficiency and fluorescence microscopy analyses determined that the synthesis of chitin, a fungal-cell-wall polysaccharide, was the target of 4-cyclopentene-1,3-dione. This fungal-specific mechanism was consistent with a 22–70-fold reduction in antibacterial activity. Overall, we identified the agricultural waste product of specific cultivars of feijoa peels as a source of potential high-value antifungal compounds