RNA interference of peroxisome-related genes inC. elegans: a new model for human peroxisomal disorders

Abstract

RNA-mediated interference (RNAi) for the posttranscriptional silencing of genes was used to evaluate the importance of various peroxisomal enzymes and peroxins for the development of Caenorhabditis elegans and to compare the roles of these proteins in the nematode to their roles in yeasts and humans. The nematode counterparts of the human ATP-binding cassette half-transporters, the enzymes alkyldihydroxyacetonephosphate synthase and Δ3,5-Δ 2,4-dienoyl-CoA isomerase, the receptors for peroxisomal membrane and matrix proteins (Pex19p and Pex5p), and components of the docking and translocation machineries for matrix proteins (Pex13p and Pex12p) are essential for the development of C. elegans. Unexpectedly, RNAi silencing of the acyl-CoA synthetase-mediated activation of fatty acids, the α- and β-oxidation of fatty acids, the intraperoxisomal decomposition of hydrogen peroxide, and the peroxins Pex1p, Pex2p, and Pex6p had no apparent effect on C. elegans development. The described analysis of functional gene knockouts through RNAi provides a basis for the use of C. elegans as a valuable model system with which to study the molecular and physiological defects underlying the human peroxisomal disorders.

Lack of Peroxisomal Catalase Causes a Progeric Phenotype in Caenorhabditis elegans

“…The ⌬ctl-2 mutant of C. elegans represents a convenient model not only for the study of aging but possibly also for the study of the human diseases acatalasemia and hypocatalasemia (23,43,44). Our results support and extend recent findings that peroxisomes not only have important roles in cell metabolism but also are involved in the developmental processes of eukaryotic organisms (23,43,25). …”

“…A previous attempt to engage CTL-1 directly in the control of aging in C. elegans was unsuccessful (21). Molecular features of the catalase gene locus in C. elegans, namely the presence of different catalase genes exhibiting a high level of sequence identity, make it difficult, if not impossible, to use the results of methods such as RNA interference (4,5,23) to permit definitive statements on the roles of individual catalases in the aging process in C. elegans. Here, using C. elegans strains mutated for individual catalase genes, we present evidence directly im- (Fig.…”

Modeling human peroxisome biogenesis disorders in the nematodeCaenorhabditis elegans

“…The homolog for PEX5 (prx-5/C34C6.6) binds to the peroxisomal targeting signal 1 in a yeast two-hybrid system, supporting its designation as the PEX5 homolog (Gurvitz et al, 2000). The C. elegans homologs for PEX2, PEX12, PEX13 and PEX19 were also identified by Petriv et al (Petriv et al, 2002). The C. elegans homologs of PEX1, PEX5, PEX6, PEX12 (prx-12/F08B12.2) and PEX13 (prx-13/F32A5.6) show the greatest sequence conservation, which is more than 50% similar over the entire (Li et al, 2002).…”

“…In both cases, the broad scope of the screens permitted examination of only gross phenotypes, which were not pursued in detail. Recently, resulted in a developmental delay and a greatly reduced Journal of Cell Science 116 (9) percentage of adult progeny 3 days following injection of dsRNA homologous to these genes (Petriv et al, 2002). The authors were not able to specify whether this was due to delayed development or to an arrest in development.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…This suggested a previously unrecognized conservation at the central amino acid X 3 , which was consistently found to present with large and hydrophobic properties (Petriv et al, 2002;Reumann, 2004;Kunze et al, 2011). In a reporter construct harboring the N-terminus of rat thiolase, the functionality of the PTS2 was destroyed by a substitution of residue X 3 with a negatively or positively charged amino acid (Kunze et al, 2011).…”