Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX

Abstract

Although external beam radiation therapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histological analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single cell RNA-seq data revealed that neural cell vulnerability stems from heightened expression of pro-apoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, pro-apoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by pro-apoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. Based on these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM or BID via direct or upstream mechanisms is expected to ameliorate neurocognitive impairment in pediatric CNS tumor patients.

Synergistic Antitumor Effects of 177Lu-Octreotide Combined with an ALK Inhibitor in a High-Risk Neuroblastoma Xenograft Model

“…After statistical analysis of the ∆Ct values (treated vs. control), only the combination treatment yielded a significant effect on the transcriptional response of genes within the Bcl-2 family (Table 1). Proteins of the Bcl-2 family are essential for apoptotic cell death in health and disease through different mechanisms [64][65][66][67]. Functionally categorized as pro-apoptotic or anti-apoptotic proteins within the Bcl-2 family, the imbalance of concentrations leads to cell survival or death [64,65].…”

In situ architecture of Opa1-dependent mitochondrial cristae remodeling

“…Biological replicates indicate assay performed on different flasks of MEF cell culture grown under the same condition and passage number. Statistical analysis was performed using a two-way ANOVA with Holm–Sidak’s correction for multiple hypothesis since the data were normally distributed (Fraser et al, 2022 ; Singh et al, 2023 ). All statistical analyses were performed in Prism 9 GraphPad software.…”

In situarchitecture of Opa1-dependent mitochondrial cristae remodeling

“…condition and passage number. Statistical analysis was performed using a two-way ANOVA with Holm-Sidak's correction for multiple hypothesis since the data were normally distributed (Fraser et al, 2022;Singh et al, 2023). All statistical analyses were performed in Prism 9 GraphPad software.…”