Functional sequestration of MOAG-2/LIR-3 by polyglutamine expansion proteins
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2500
ORGANISM(S): Caenorhabditis elegans
SUBMITTER: Victor Guryev
PROVIDER: E-MTAB-4172 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Functional sequestration of MOAG-2/LIR-3 by polyglutamine expansion proteins
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Project description:Purpose: To delineate mechanisms underlying lipid storage in LDs, we compared the transcriptomes of cells cultivated under three lipid-accumulating conditions. Methods: PD630 mRNA profiles of 3 different conditions (normal condition and LDs acculation conditions) were generated by deep sequencing, using Solid platform. The sequence reads were mapped by using Bowtie followed by Cufflinks. Results: Most genes were either expressed under all three conditions (6,759 genes) or under at least one condition (7,770 genes), but 1,177 genes were not expressed under any of these conditions. We observed a marked response 3 h after cells were transferred from NB to MSM; 56.99% of the genes were up-regulated and 30.32% were down-regulated, with 21.15% being up-regulated more than 2-fold and 9.36% being down-regulated more than 2-fold Conclusions: Genes in category J (translation, ribosomal structure and biogenesis) were significantly up-regulated (p-value 5.05E-20, two-tailed Chi-square test), while genes in category K (transcription), G (carbohydrate transport and metabolism) and C (energy production and conversion) were down-regulated (p-values: 6.0E-07, 8.08E-06 and 4.56E-05, respectively, two-tailed Chi-square test). Increased expression of ribosomal proteins is consistent with number of genes (56.99%) up-regulated in the MSM3 treatment. This decrease in energy production and conversion is consistent with inhibition of cell division and lipid accumulation in MSM. PD630 mRNA profiles of 3 different conditions (normal condition and LDs acculation conditions) were generated by deep sequencing, using Solid platform.
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Project description:Polyglutamine (polyQ) amyloid fibrils are observed in disease tissue and have been implicated as toxic agents responsible for neurodegeneration in expanded CAG repeat diseases such as Huntington's disease. Despite intensive efforts, the mechanism of amyloid toxicity remains unknown. As a novel approach to probing polyQ toxicity, we investigate here how some cellular and physical properties of polyQ amyloid vary with the chirality of the glutamine residues in the polyQ. We challenged PC12 cells with small amyloid fibrils composed of either L- or D-polyQ peptides and found that D-fibrils are as cytotoxic as L-fibrils. We also found using fluorescence microscopy that both aggregates effectively seed the aggregation of cell-produced L-polyQ proteins, suggesting a surprising lack of stereochemical restriction in seeded elongation of polyQ amyloid. To investigate this effect further, we studied chemically synthesized D- and L-polyQ in vitro. We found that, as expected, D-polyQ monomers are not recognized by proteins that recognize L-polyQ monomers. However, amyloid fibrils prepared from D-polyQ peptides can efficiently seed the aggregation of L-polyQ monomers in vitro, and vice versa. This result is consistent with our cell results on polyQ recruitment but is inconsistent with previous literature reports on the chiral specificity of amyloid seeding. This chiral cross-seeding can be rationalized by a model for seeded elongation featuring a "rippled β-sheet" interface between seed fibril and docked monomers of opposite chirality. The lack of chiral discrimination in polyQ amyloid cytotoxicity is consistent with several toxicity mechanisms, including recruitment of cellular polyQ proteins.
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