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Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination

Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. However, the role of endogenously synthesized creatine on CNS development and function remains poorly understood. Here, magnetic resonance spectro...

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Autores principales: Rosko, Lauren M., Gentile, Tyler, Smith, Victoria N., Manavi, Zeeba, Melchor, George S., Hu, Jingwen, Shults, Nataliia V., Albanese, Chris, Lee, Yichien, Rodriguez, Olga, Huang, Jeffrey K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9962777/
https://www.ncbi.nlm.nih.gov/pubmed/36732069
http://dx.doi.org/10.1523/JNEUROSCI.2120-21.2022
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author Rosko, Lauren M.
Gentile, Tyler
Smith, Victoria N.
Manavi, Zeeba
Melchor, George S.
Hu, Jingwen
Shults, Nataliia V.
Albanese, Chris
Lee, Yichien
Rodriguez, Olga
Huang, Jeffrey K.
author_facet Rosko, Lauren M.
Gentile, Tyler
Smith, Victoria N.
Manavi, Zeeba
Melchor, George S.
Hu, Jingwen
Shults, Nataliia V.
Albanese, Chris
Lee, Yichien
Rodriguez, Olga
Huang, Jeffrey K.
author_sort Rosko, Lauren M.
collection PubMed
description Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. However, the role of endogenously synthesized creatine on CNS development and function remains poorly understood. Here, magnetic resonance spectroscopy of adult mouse brains from both sexes revealed creatine synthesis is dependent on the expression of the enzyme, guanidinoacetate methyltransferase (GAMT). To identify Gamt-expressed cells, and how Gamt affects postnatal CNS development, we generated a mouse line by knocking-in a GFP, which is expressed on excision of Gamt. We found that Gamt is expressed in mature oligodendrocytes during active myelination in the developing postnatal CNS. Homozygous deletion of Gamt resulted in significantly reduced mature oligodendrocytes and delayed myelination in the corpus callosum. Moreover, the absence of endogenous creatine resulted in altered AMPK signaling in the brain, reduced brain creatine kinase expression in cortical neurons, and signs of axonal damage. Experimental demyelination in mice after tamoxifen-induced conditional deletion of Gamt in oligodendrocyte lineage cells resulted in delayed maturation of oligodendrocytes and myelin coverage in lesions. Moreover, creatine and cyclocreatine supplementation can enhance remyelination after demyelination. Our results suggest endogenously synthesized creatine controls the bioenergetic demand required for the timely maturation of oligodendrocytes during postnatal CNS development, and that delayed myelination and altered CNS energetics through the disruption of creatine synthesis might contribute to conditions, such as CCDS. SIGNIFICANCE STATEMENT Cerebral creatine deficiency syndrome is a rare disease of inborn errors in metabolism, which is characterized by intellectual delays, seizures, and autism-like behavior. We found that oligodendrocytes are the main source of endogenously synthesized creatine in the adult CNS, and the loss of endogenous creatine synthesis led to delayed myelination. Our study suggests impaired cerebral creatine synthesis affects the timing of myelination and may impact brain bioenergetics.
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spelling pubmed-99627772023-02-26 Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination Rosko, Lauren M. Gentile, Tyler Smith, Victoria N. Manavi, Zeeba Melchor, George S. Hu, Jingwen Shults, Nataliia V. Albanese, Chris Lee, Yichien Rodriguez, Olga Huang, Jeffrey K. J Neurosci Research Articles Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. However, the role of endogenously synthesized creatine on CNS development and function remains poorly understood. Here, magnetic resonance spectroscopy of adult mouse brains from both sexes revealed creatine synthesis is dependent on the expression of the enzyme, guanidinoacetate methyltransferase (GAMT). To identify Gamt-expressed cells, and how Gamt affects postnatal CNS development, we generated a mouse line by knocking-in a GFP, which is expressed on excision of Gamt. We found that Gamt is expressed in mature oligodendrocytes during active myelination in the developing postnatal CNS. Homozygous deletion of Gamt resulted in significantly reduced mature oligodendrocytes and delayed myelination in the corpus callosum. Moreover, the absence of endogenous creatine resulted in altered AMPK signaling in the brain, reduced brain creatine kinase expression in cortical neurons, and signs of axonal damage. Experimental demyelination in mice after tamoxifen-induced conditional deletion of Gamt in oligodendrocyte lineage cells resulted in delayed maturation of oligodendrocytes and myelin coverage in lesions. Moreover, creatine and cyclocreatine supplementation can enhance remyelination after demyelination. Our results suggest endogenously synthesized creatine controls the bioenergetic demand required for the timely maturation of oligodendrocytes during postnatal CNS development, and that delayed myelination and altered CNS energetics through the disruption of creatine synthesis might contribute to conditions, such as CCDS. SIGNIFICANCE STATEMENT Cerebral creatine deficiency syndrome is a rare disease of inborn errors in metabolism, which is characterized by intellectual delays, seizures, and autism-like behavior. We found that oligodendrocytes are the main source of endogenously synthesized creatine in the adult CNS, and the loss of endogenous creatine synthesis led to delayed myelination. Our study suggests impaired cerebral creatine synthesis affects the timing of myelination and may impact brain bioenergetics. Society for Neuroscience 2023-02-15 /pmc/articles/PMC9962777/ /pubmed/36732069 http://dx.doi.org/10.1523/JNEUROSCI.2120-21.2022 Text en Copyright © 2023 Rosko et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Articles
Rosko, Lauren M.
Gentile, Tyler
Smith, Victoria N.
Manavi, Zeeba
Melchor, George S.
Hu, Jingwen
Shults, Nataliia V.
Albanese, Chris
Lee, Yichien
Rodriguez, Olga
Huang, Jeffrey K.
Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination
title Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination
title_full Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination
title_fullStr Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination
title_full_unstemmed Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination
title_short Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination
title_sort cerebral creatine deficiency affects the timing of oligodendrocyte myelination
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9962777/
https://www.ncbi.nlm.nih.gov/pubmed/36732069
http://dx.doi.org/10.1523/JNEUROSCI.2120-21.2022
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