Nuclear Profilin-1 for DNA Damage Repair Is Involved in Phagocytic Impairment of Senescent Microglia

Abstract

Accumulation of DNA damage is a hallmark of cellular senescence and plays a critical role in brain aging. Although the DNA damage repair mechanisms are crucial in cellular senescence, they are not well understood in microglia. In this study, we found that profilin-1 (PFN1), an actin-binding protein, relocates from the cytoplasm to the nucleus in response to DNA double-strand breaks (DSBs) induced by doxorubicin. This nuclear PFN1 subsequently translocates back to the cytoplasm during the recovery period. In response to DSBs, we detected enhanced expression of genes associated with nonhomologous end joining (NHEJ), but not with homologous recombination (HR), along with increased nuclear F-actin accumulation. However, this repair process is compromised when PFN1 is either knocked down or its nuclear transport is blocked. Notably, in DNA damage-induced senescent microglia, increased nuclear localization of PFN1 and nuclear F-actin formation are associated with phagocytic dysfunction. Both ex vivo aged microglia and publicly available single-cell RNA sequencing data from aged mouse brains recapitulate the in vitro findings described above. Despite cytochalasin D treatment for actin depolymerization, the return of PFN1 to the cytoplasm was not facilitated due to its aggregation. We propose that PFN1 plays an important role in DNA damage repair in microglia. In addition, the dysregulation of the nucleocytoplasmic balance of PFN1 alongside DNA damage accumulation may contribute to the phagocytic impairment of microglia in the aged brain.