Unknown,Transcriptomics,Genomics,Proteomics

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A yeast-based assay identifies drugs active against human mitochondrial disorders

ABSTRACT: Transcriptome profile of S. cerevisiae strain MC6 (deletion mutant for the ATP synthase assembly factor FMC1, used as a yeast model of mitochondrial disease) grown at 35C in rich galactose media supplemented with either 1.25uM chlorhexidine (a drug identified in a yeast-based screen with potential therapeutic effects) or DMSO as a control. The isogenic wild-type strain (MC1) was included as a control. Strains originate from http://www.ncbi.nlm.nih.gov/pubmed/11096112 and the arrays used were yeast tiling microarrays from Affymetrix.

ORGANISM(S): Saccharomyces cerevisiae

SUBMITTER: Charles Girardot

PROVIDER: E-TABM-1176 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A yeast-based assay identifies drugs active against human mitochondrial disorders.

Couplan Elodie E Aiyar Raeka S RS Kucharczyk Roza R Kabala Anna A Ezkurdia Nahia N Gagneur Julien J St Onge Robert P RP Salin Bénédicte B Soubigou Flavie F Le Cann Marie M Steinmetz Lars M LM di Rago Jean-Paul JP Blondel Marc M

Proceedings of the National Academy of Sciences of the United States of America 20110629 29

Due to the lack of relevant animal models, development of effective treatments for human mitochondrial diseases has been limited. Here we establish a rapid, yeast-based assay to screen for drugs active against human inherited mitochondrial diseases affecting ATP synthase, in particular NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. This method is based on the conservation of mitochondrial function from yeast to human, on the unique ability of yeast to survive without production of ...[more]

PMID: 21715656

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Project description:Toxoplasma gondii is an obligate intracellular protozoan parasite whose rapid lytic replication cycles define its pathogenicity. We identified a temperature sensitive growth mutant, FV-P6, which irreversibly arrests before the middle of the G1 stage of the tachyzoite cell cycle. This arrest is caused by a point mutation in a gene conserved across eukaryotes, Cactin, whose product localizes to the nucleus. To elucidate the role of TgCactin we performed genome-wide expression profiling of FV-P6 mutant parasites at 35C and 40C, as well as FV-P6 complemented with a wild-type Cactin encoding cosmid (TOXO93 or comp) and as a pseudo-diploid wild-type line encoding both the wild-type and mutant Cactin locus (S4.2), also at both temperatures. Besides the expected G1 expression profile, many genes associated with the extracellular state as well as with the bradyzoite cyst stage were identified. Consistent with these profiles were the expression of AP2 transcription factors typically associated with extracellular and bradyzoite stage parasites. This suggests a role for TgCactin in control of gene expression. Since TgCactin does not contain any functionally defined domains we reasoned TgCactin exerts its function through interactions with other proteins. In support of this model we demonstrated that TgCactin is present in a protein complex and can oligomerize. Taken together, these results suggest that TgCactin acts as a pivotal protein potentially regulating gene expression at several transition points in parasite development. The role of Cactin in G1 progression of Toxoplasma gondii tachyzoites was assessed by expression profiling a temperature senstive mutant of Cactin at both the permissive (35C) as well as the restrictive (40C) temperature. Controls under the same temperature conditions inlcude the mutant line complemented with a wild-type Cactin allele encoded on a cosmid and a wild-type parasite line expressing an additional, mutant allele of Cactin (pseudo-diploid line).

Dataset Information

A yeast-based assay identifies drugs active against human mitochondrial disorders

Publications

A yeast-based assay identifies drugs active against human mitochondrial disorders.

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