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Short-Term Cuprizone Feeding Induces Selective Amino Acid Deprivation with Concomitant Activation of an Integrated Stress Response in Oligodendrocytes

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Abstract

Cuprizone [bis(cyclohexylidenehydrazide)]-induced toxic demyelination is an experimental approach frequently used to study de- and re-myelination in the central nervous system. In this model, mice are fed with the copper chelator cuprizone which leads to oligodendrocyte apoptosis and subsequent microgliosis, astrocytosis, and demyelination. The underlying mechanisms of cuprizone-induced oligodendrocyte death are still unknown. We analysed differences in amino acid levels after short-term cuprizone exposure (i.e., 4 days). Furthermore, an amino acid response (AAR) pathway activated in oligodendrocytes after cuprizone intoxication was evaluated. Short-term cuprizone exposure resulted in a selective decrease of alanine, glycine, and proline plasma levels, which was paralleled by an increase of apoptotic cells in the liver and a decrease of alanine aminotransferase in the serum. These parameters were paralleled by oligodendrocyte apoptosis and the induction of an AAR with increased expression of the transcription factors ATF-3 and ATF-4 (activating transcription factor-3 and -4). Immunohistochemistry revealed that ATF-3 is exclusively expressed by oligodendrocytes and localized to the nuclear compartment. Our results suggest that cuprizone-induced liver dysfunction results in amino acid starvation and in consequence to the activation of an AAR. We propose that this stress response modulates oligodendrocyte viability in the cuprizone animal model.

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Acknowledgments

This study was partly supported by START Grants of the Medical Faculty, RWTH Aachen (TC). We would like to thank Helga Helten and Sandra Vidal de la Torre for their excellent technical assistance.

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  1. Faculty of Medicine, Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Johannes Goldberg, Moritz Daniel, Yasemin van Heuvel, Marion Victor, Cordian Beyer, Tim Clarner & Markus Kipp

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  1. Johannes Goldberg
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  2. Moritz Daniel
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Correspondence to Markus Kipp.

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Goldberg J and Daniel M have contributed equally to this work as first authors and T Clarner and Kipp M have contributed equally to this work as last authors.

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Goldberg, J., Daniel, M., van Heuvel, Y. et al. Short-Term Cuprizone Feeding Induces Selective Amino Acid Deprivation with Concomitant Activation of an Integrated Stress Response in Oligodendrocytes. Cell Mol Neurobiol 33, 1087–1098 (2013). https://doi.org/10.1007/s10571-013-9975-y

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