RTAD-09 NEUROLOGIC DEFECTS IN AN APE2 TRANSGENIC MOUSE MODEL OF RADIATION-INDUCED BRAIN INJURY

Abstract

Radiation-induced brain injury (RIBI) affects 50–90% of patients undergoing brain irradiation and remains a major dose-limiting toxicity of radiotherapy. Although DNA double-strand breaks have been extensively studied, oxidative stress–associated mechanisms remain incompletely defined. Here, we investigate the role of the neuron-specific DNA repair enzyme apurinic/apyrimidinic endonuclease 2 (APE2) in RIBI using murine models and human brain biopsy specimens. We demonstrate that radiation exposure significantly upregulates APE2 expression in neurons in both murine RIBI models (9 Gy) and patient samples. To determine causality, we generated a conditional APE2 transgenic mouse model. These mice developed progressive neurological deficits, including anxiety-like behavior, impaired motor function, sensory abnormalities, and deficits in spatial learning and memory, as assessed by elevated plus maze, grip strength, and Barnes maze testing. Notably, APE2 transgenic mice exhibited severe ataxia and early mortality by 15 weeks. MRI revealed marked neuroanatomical abnormalities, including global brain volume reduction, with region-specific vulnerability in the cerebellum and cortex, and white matter loss. Proteomic analysis identified motor neuron disease associated proteins ERLIN1/2 as key APE2-interacting partners, which was validated by co-immunoprecipitation and immunofluorescence. Domain mapping studies suggest that APE2 upregulation disrupts ERLIN1/2 complex integrity. The phenotype of APE2 transgenic mice closely recapitulates the motor deficits seen in ERLIN1-mutant patients, suggesting a link between APE2 upregulation and neuronal dysfunction. Collectively, these findings identify APE2 as a central mediator of RIBI and uncover a novel mechanism for APE2 beyond its role in DNA damage repair to disrupt ERLIN1/2 complex function to drive neurodegeneration. These studies highlight APE2 as a promising therapeutic target for preventing radiation-induced brain injury.