α-synucleinopathy exerts sex-dimorphic effects on the multipurpose DNA repair/redox protein APE1 in mice and humans

Lewy body disorders are characterized by oxidative damage to DNA and inclusions rich in aggregated forms of alpha-synuclein. Among other roles, apurinic/apyrimidinic endonuclease 1 (APE1) repairs oxidative DNA damage, and APE1 polymorphisms have been linked to cases of Lewy body disorders. However, the link between APE1 and alpha-synuclein is unexplored. We report that knockdown or inhibition of APE1 amplified inclusion formation in primary hippocampal cultures challenged with preformed alpha-synuclein fibrils. Fibril infusions into the mouse olfactory bulb/anterior olfactory nucleus (OB/AON) elicited a modest decrease in APE1 expression in the brains of male mice but an increase in females. Similarly, men with Lewy body disorders displayed lower APE1 expression in the OB and amygdala compared to women. Preformed fibril infusions of the mouse OB/AON induced more robust base excision repair of DNA lesions in females than males. No fibril-mediated loss of APE1 expression was observed in male mice when the antioxidant N-acetylcysteine was added to their diet. These findings reveal a potential sex-biased link between alpha-synucleinopathy and APE1 in mice and humans. Further studies are warranted to determine how this multifunctional protein modifies alpha-synuclein inclusions and, conversely, how alpha-synucleinopathy and biological sex interact to modify APE1.

Automated summary

This study reveals a potential sex-biased link between alpha-synucleinopathy and APE1 in mice and humans, suggesting that APE1 may play a role in the formation of alpha-synuclein inclusions. Further studies are needed to understand how APE1 modifies alpha-synuclein inclusions and how alpha-synucleinopathy and biological sex interact to modify APE1.