A Connection Between DNA Repair Protein APE1, Alpha‐Synucleinopathy, and Biological Sex in Rodents and Humans

Abstract

Lewy body disorders are characterized by proteostatic and redox disequilibrium, leading to deposition of α‐synuclein in hallmark inclusions and oxidative damage to DNA. One common pathway for repair of oxidative DNA damage is base excision repair (BER), which involves the coordinated activity of several enzymes, including apurinic/apyrimidinic endonuclease 1 (APE1). The main goal of this study was to assess APE1 in rodents and humans with α‐synucleinopathy, and to test the functional impact of APE1 in the preformed α‐synuclein fibril model. First, we report that knockdown of APE1 with two independent shRNA sequences or inhibition of APE1 DNA repair activity increased inclusions bearing pathologically‐phosphorylated α‐synuclein (pSer129) in preformed fibril‐treated primary hippocampal cultures. Second, we examined APE1 expression in a mouse model of limbic‐centered α‐synucleinopathy, in which α‐synuclein fibrils are infused into the olfactory bulb/anterior olfactory nucleus (OB/AON). Six months later, we observed a fibril‐induced decrease in APE1 expression in the brains of male mice and an increase in females.Similar sex‐opposing patterns were noted for APE1 mRNA expression. Third, we demonstrated that the loss of APE1 in fibril‐infused male mice in vivo is mediated by oxidative stress, as APE1 loss was abolished by dietary administration of the antioxidant N‐acetylcysteine. Fourth, OB/AON tissues harvested from fibril‐infused male mice displayed higher cleavage of synthetic DNA lesions on a biochip than tissues collected in parallel from fibril‐infused female mice. However, OB/AON tissues harvested from fibril‐infused female mice had higher DNA repair activity compared to males. Assessments of open field activity measures and sucrose preference revealed a negative behavioral impact of α‐synuclein fibril infusions in male but not female mice. Fifth, men with Lewy body disorders displayed lower APE1 expression in the OB and amygdala compared to women with Lewy body disorders, similar to fibril‐infused mice. Finally, we infused α‐synuclein fibrils into the OB/AON of transgenic APE1 overexpressing rats and observed a reduction in pSer129 levels in male and female brains compared to fibril‐infused wildtype rats. Preliminary data suggest that APE1 overexpression in fibril‐infused rats improved olfaction and anxiety measures, especially in males. These findings reveal a sex‐biased impact of limbic α‐synucleinopathy on APE1 expression and function but also suggest that APE1 overexpression attenuates α‐synucleinopathy in both sexes.