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Marilyn Parsons , Ph.D.

Molecular Analysis of the Glycosome
Novel structures and unique organelles are characteristic of protozoan parasites. This project examines an organelle unique to trypanosomes, Leishmania, and related parasites: the glycosome. This organelle lacks a genome of its own. The glycosome is the site of the glycolytic pathway, hence its name. Additionally, it is the site of several other important metabolic pathways: ether-lipid synthesis, beta-oxidation of fatty acids, and purine salvage. The importance of the glycosome in T. brucei is clear: these parasites, when in the mammalian host, derive all of their energy from glycolysis. In contrast, in Leishmania, energy generation through glycolysis is complemented by mitochondrial oxidative phosphorylation. However, the major surface glycoconjugate, LPG, possesses an ether-lipid anchor, presumably synthesized in the glycosome. 

Our laboratory has characterized glycosomal targeting sequences that direct the post-translational import of proteins into the glycosome. We used this information to develop a positive genetic selection for mutant parasites with defects in glycosomal biogenesis and have completed initial gene rescue studies that identified a gene, LdPEX2, involved in biogenesis of the organelle. This gene is a member of the PEX2 gene family, which is involved in peroxisome biogenesis. This finding strongly supported the hypothesis that glycosomes and peroxisomes share a common evolutionary origin. We have also shown that LdPEX2 is likely to be an essential gene. The low homology between PEX homologues in trypanosomatids and humans (only about 25% sequence identity) and the essential nature of PEX proteins in the parasites suggest that PEX proteins may be good targets for drug development. Toward this end, we are mapping LdPEX2, with respect to both function and topology. We have recently identified other potential PEX genes by database analysis. We are analyzing the function of T. brucei PEX gene candidates using double-stranded RNA interference (RNAi). Our studies have shown that degradation of the PEX14 mRNA leads kills both the bloodstream and procyclic forms of the parasite. We have identified several additional PEX gene candidates in Leishmania, including several of the RING proteins, and are currently performing confirmatory functional and protein interactions studies.

This project is supported by a grant from the National Institutes of Health, R01 AI22635, Marilyn Parsons, Principal Investigator.

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