Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

Molina-Gonzalez, I.; Holloway, R. K.; Jiwaji, Z.; Dando, O. R.; Emelianova, K.; Lloyd, A. F.; Forbes, L. H.; Mahmood, A.; Skripuletz, T.; Gudi, V.; Febery, J.; Johnson, J.; Fowler, J.; Kuhlmann, T.; Williams, A.; Chandran, S.; Stangel, M.; Howden, A. J.; Hardingham, G.; Miron, V. E.

doi:10.1101/2022.10.04.510850

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bioRxiv · 10.1101/2022.10.04.510850

Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

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Abstract

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand1,2. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

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Molina-Gonzalez, I., Holloway, R. K., Jiwaji, Z., Dando, O. R., Emelianova, K., Lloyd, A. F., Forbes, L. H., Mahmood, A., Skripuletz, T., Gudi, V., Febery, J., Johnson, J., Fowler, J., Kuhlmann, T., Williams, A., Chandran, S., Stangel, M., Howden, A. J., Hardingham, G., Miron, V. E.. 2022-10-06. Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration. https://doi.org/10.1101/2022.10.04.510850

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