title: Short-term cuprizone feeding induces selective amino acid deprivation with concomitant activation of an integrated stress response in oligodendrocytes.
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.
authors: Faculty of Medicine, Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
authors: Johannes
authors: J
authors: Goldberg
authors: Moritz
authors: M
authors: Daniel
authors: Yasemin
authors: Y
authors: van Heuvel
authors: Marion
authors: M
authors: Victor
authors: Cordian
authors: C
authors: Beyer
authors: Tim
authors: T
authors: Clarner
authors: Markus
authors: M
authors: Kipp
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000097:blood / Q000172:deficiency; D000818:Animals; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003471:Cuprizone / Q000008:administration & dosage / Q000633:toxicity*; D005247:Feeding Behavior; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D013312:Stress, Physiological / Q000187:drug effects*; D013997:Time Factors
chemical_list: D051700:Activating Transcription Factor 3; D000596:Amino Acids; C103002:Atf3 protein, mouse; C081452:Atf4 protein, mouse; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D018992:Myelin-Associated Glycoprotein; D051701:Activating Transcription Factor 4; D003471:Cuprizone
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