Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression

ABSTRACT: Transcriptional profiling of C. elegans strains grown in the presence and absence of ethosuximide. Two mutant alleles of dnj-14 (tm3223 and ok237) and two wild type control strains (N2 and CZ1200) were analysed. dnj-14 is the worm orthologue of the human DNAJC5 gene, mutations in which cause the neurodegenerative disease, adult onset neuronal ceroid lipofucinosis. Ethosuximide ameliorates neurodegenerative phenotypes in the dnj-14 model and also in C. elegans neurodegenerative disease models based on expression of human mutant Tau and TDP-43 proteins. It is hoped that transcriptional profiling of the effect of ethosuximide on gene expression in both wild type and mutant strains might help to identify the mechanism by which ethosuximide exerts its generally neuroprotective mechanism of action. The untreated control samples of this study are also used in the experiment with accession E-MTAB-3147.

ORGANISM(S): Caenorhabditis elegans

SUBMITTER: Hannah McCue

PROVIDER: E-MTAB-3919 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Microglia, the resident immune cells of the central nervous system (CNS), have two distinct phenotypes in the developing brain: amoeboid form, known to be amoeboid microglial cells (AMC) and ramified form, known to be ramified microglial cells (RMC) alongside several intermediate forms. The AMC are characterized by being proliferative, phagocytic and migratory whereas the RMC are quiescent and exhibit a slow turnover rate. The AMC transform into RMC with advancing age, and this transformation is indicative of the gradual shift in the microglial functions. Both AMC and RMC respond to CNS inflammation, and they become hypertrophic when they are activated by trauma, infection or neurodegenerative stimuli. The molecular mechanisms and functional significance of morphological transformation of microglia during normal development and in disease conditions is not clear. It is hypothesized that AMC and RMC are functionally regulated by a specific set of genes encoding various signaling molecules and transcription factors. To address this, we carried out cDNA microarray analysis using lectin-labeled AMC and RMC isolated from frozen tissue sections of the corpus callosum of 5-day and 4-week old rat brain respectively, by laser capture microdissection (LCM). The global gene expression profiles of both microglial phenotypes were compared and the differentially expressed genes in AMC and RMC were clustered based on their functional annotations. This genome wide comparative analysis helps in identifying genes that are specific to AMC and RMC. The novel and specific molecules identified in both microglial phenotypes can be targeted for therapeutic purposes in developing and adult brain diseases. We used microarrays to identify the genes specific to amoeboid and ramified microglia. RNA was isolated from the laser-captured amoeboid and ramified microglia from the corpus callosum of 5-day and 4-week old rat brain. The RNA was hybridised onto Affymetrix Rat 230 2.0 array.

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Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression

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