MicroRNAs (miRNAs) play an important role in human brain development and maintenance. To search for miRNAs that may be involved in the pathogenesis of Parkinsons disease (PD), we utilized miRNA microarrays to identify potential gene expression changes in 115 annotated miRNAs in PD-associated Caenorhabditis elegans models that either overexpress human A53T alpha-synuclein or have mutations within the vesicular catecholamine transporter (cat-1) or parkin (pdr-1) ortholog. Here, we show that 12 specific miRNAs are differentially regulated in the animals overexpressing alpha-synuclein, five in cat-1, and three in the pdr-1 mutants. The family of miR-64 and miR-65 are co-underexpressed in the alpha-synuclein transgenic and cat-1 strains, and members of let-7 family co-underexpressed in the alpha-synuclein and pdr-1 strains; mdl-1 and ptc-1 genes are target candidates for miR-64 and miR-65 and are overexpressed in alpha-synuclein transgenic as well as miR-64/65 (tm3711) knockout animals. These results indicate that miRNAs are differentially expressed in C. elegans PD models and suggest a role for these molecules in disease pathogenesis.
Our data indicate that although inhibition of PDI suppresses excessive protein folding and ER stress, it induces clearance of aggregated αSyn by autophagy as an alternative degradation pathway. These findings suggest a novel model explaining the contribution of ER dysfunction to MPP(+)-induced neurodegeneration and highlight PDI inhibitors as potential treatment in diseases involving protein misfolding. Antioxid. Redox Signal. 25, 485-497.
Methylmercury (MeHg) is a persistent environmental and dietary contaminant that causes serious adverse developmental and physiologic effects at multiple cellular levels. In order to understand more fully the consequences of MeHg exposure at the molecular level, we profiled gene and miRNA transcripts from the model organism Caenorhabditis elegans. Animals were exposed to MeHg (10µM) from embryo to larval 4 (L4) stage and RNAs were isolated. RNA-seq analysis on the Illumina platform revealed 541 genes up- and 261 genes down-regulated at a cutoff of 2-fold change and false discovery rate-corrected significance q < 0.05. Among the up-regulated genes were those previously shown to increase under oxidative stress conditions including hsp-16.11 (2.5-fold), gst-35 (10.1-fold), and fmo-2(58.5-fold). In addition, we observed up-regulation of 6 out of 7 lipocalin related (lpr) family genes and down regulation of 7 out of 15 activated in blocked unfolded protein response (abu) genes. Gene Ontology enrichment analysis highlighted the effect of genes related to development and organism growth. miRNA-seq analysis revealed 6–8 fold down regulation of mir-37-3p, mir-41-5p, mir-70-3p, and mir-75-3p. Our results demonstrate the effects of MeHg on specific transcripts encoding proteins in oxidative stress responses and in ER stress pathways. Pending confirmation of these transcript changes at protein levels, their association and dissocation characteristics with interaction partners, and integration of these signals, these findings indicate broad and dynamic mechanisms by which MeHg exerts its harmful effects.
Methylmercury (MeHg) is a persistent environmental pollutant that occurs in the food chain, at occupational sites, and via medical procedures. Exposure in humans and animal models results in renal, neuro, and reproductive toxicities. In this study, we demonstrate that chronic exposure to MeHg (10μM) causes epigenetic landscape modifications of histone H3K4 trimethylation (H3K4me3) marks in Caenorhabditis elegans using chromatin immuno-precipitation sequencing (ChIP-seq). The modifications correspond to the locations of 1467 genes with enhanced and 508 genes with reduced signals. Among enhanced genes are those encoding glutathione-S-transferases, lipocalin-related protein and a cuticular collagen. ChIP-seq enhancement of these genes was confirmed with increased mRNA expression levels revealed by qRT-PCR. Furthermore, we observed enhancement of H3K4me3 marks in these genes in animals exposed to MeHg in utero and assayed at L4 stage. In utero exposure enhanced marks without alterations in mRNA expression except for the lpr-5 gene. Finally, knockdown of lipocalin-related protein gene lpr-5, which is involved in intercellular signaling, and cuticular collagen gene dpy-7, structural component of the cuticle, by RNA interference (RNAi) resulted in increased lethality of animals after MeHg exposure. Our results provide new data on the epigenetic landscape changes elicited by MeHg exposure, as well as describe a unique model for studying in utero effects of heavy metals. Together, these findings may help to understand the toxicological effects of MeHg at the molecular level.
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