Tetrahydrobiopterin restores oligodendrocyte maturation after hypoxic white matter injury by reprogramming translational output
Year: 2026
Type: preprint
Abstract: ABSTRACT Background Complex congenital heart defects (CHDs) are frequently associated with chronic cerebral hypoxemia, leading to impaired white matter maturation. One proposed mechanism involves hypoxia-induced disruption of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), resulting in oxidative stress and impaired oligodendrocyte (OL) development. While our previous studies found BH4 supplementation improves hypoxia-induced white matter dysmaturation, the molecular mechanisms remain incompletely understood. Because OL maturation requires coordinated translational control, we hypothesized that BH4 promotes white matter maturation by restoring translation programs disrupted by hypoxia. Methods Translating Ribosome Affinity Purification sequencing (TRAP-seq) was performed on OL lineage cells isolated from transgenic ribosomal reporter mice exposed to chronic hypoxia (10.5% O₂, postnatal day 3–11) with or without daily BH4 treatment. Differential translation, weighted gene co-expression network analysis, pathway enrichment, RNAscope, and immunohistochemistry identified translational programs associated with hypoxia and BH4-mediated rescue. Results Developmental hypoxia extensively altered the OL translatome, suppressing transcripts associated with OL maturation while enriching pathways related to translational regulation and cellular stress. Network analyses identified BH4-responsive gene modules enriched for OL maturation, protein metabolism, and translation-related processes. BH4 partially reversed hypoxia-induced translational changes, restored OL maturation gene expression, and normalized nuclear localization of the lineage regulator OLIG1, consistent with recovery of maturation-associated regulatory programs. Conclusions Developmental hypoxia disrupts OL maturation through coordinated alterations in ribosome-associated gene expression and post-transcriptional regulatory pathways. BH4 promotes recovery of OL maturation programs, including restoration of translation-related networks and OLIG1 nuclear localization, providing mechanistic insight into BH4-supported white matter maturation under chronic hypoxic conditions. Research Perspective What New Question Does This Study Raise? Developmental hypoxemia in congenital heart disease remodels the oligodendrocyte translatome, raising the question of whether translational dysregulation represents a fundamental and therapeutically targetable mechanism underlying white matter dysmaturation in other forms of perinatal brain injury. What Question Should Be Addressed Next? Future studies should determine how BH4 restores ribosome-associated translation of oligodendrocyte maturation programs, establish whether these molecular changes increase myelin protein synthesis and improve long-term neurodevelopmental outcomes, and define the cross-species efficacy for clinical translation. Clinical Research Implication These findings provide a mechanistic rationale for evaluating BH4 as a neuroprotective adjunct therapy to preserve white matter development in fetuses and infants with congenital heart disease experiencing chronic cerebral hypoxemia.
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223965612