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BMC Genomics

, 16:662

Eukaryote microbial genomics

Abstract

BackgroundProtein aggregation and its pathological effects are the major cause of several neurodegenerative diseases. In Huntington’s disease an elongated stretch of polyglutamines within the protein Huntingtin leads to increased aggregation propensity. This induces cellular defects, culminating in neuronal loss, but the connection between aggregation and toxicity remains to be established.

ResultsTo uncover cellular pathways relevant for intoxication we used genome-wide analyses in a yeast model system and identify fourteen genes that, if deleted, result in higher polyglutamine toxicity. Several of these genes, like UGO1, ATP15 and NFU1 encode mitochondrial proteins, implying that a challenged mitochondrial system may become dysfunctional during polyglutamine intoxication. We further employed microarrays to decipher the transcriptional response upon polyglutamine intoxication, which exposes an upregulation of genes involved in sulfur and iron metabolism and mitochondrial Fe-S cluster formation. Indeed, we find that in vivo iron concentrations are misbalanced and observe a reduction in the activity of the prominent Fe-S cluster containing protein aconitase. Like in other yeast strains with impaired mitochondria, non-fermentative growth is impossible after intoxication with the polyglutamine protein. NMR-based metabolic analyses reveal that mitochondrial metabolism is reduced, leading to accumulation of metabolic intermediates in polyglutamine-intoxicated cells.

ConclusionThese data show that damages to the mitochondrial system occur in polyglutamine intoxicated yeast cells and suggest an intricate connection between polyglutamine-induced toxicity, mitochondrial functionality and iron homeostasis in this model system.

KeywordsPolyglutamine Iron-sulfur cluster Mitochondria Neurodegenerative disease AbbreviationspolyQStretch of polyglutamine residues

NMRNuclear magnetic resonance spectroscopy

EPRElectron paramagnetic resonance spectroscopy

DFODesferroxiamine

DETAPACDiethylenetriamine pentaacetic acid

Fe-S clusterIron-sulfur cluster

DTTDithiothreitol

EDTAEthylenediaminetetraacetic acid

D2ODeuterated water

YPDYeast extract peptone dextrose medium

SD mediaSynthetic defined media

YFPYellow fluorescent protein

WTWild type

picaPolyglutamine-induced cellular arrest

Katharina Papsdorf and Christoph J. O. Kaiser contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s12864-015-1831-7 contains supplementary material, which is available to authorized users.

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Autor: Katharina Papsdorf - Christoph J. O. Kaiser - Adrian Drazic - Stefan W. Grötzinger - Carmen Haeßner - Wolfgang Eisenrei

Fuente: https://link.springer.com/







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