Excessive disulfide bonds in Lamin A/C contribute to premature human aging.

Nuclear lamins provide structural integrity to the nuclear envelope through coiled-coil dimer meshworks. Lamin A contains a C-terminal immunoglobulin (Ig)-like domain and a cysteine-rich unstructured tail, whereas lamin C lacks the latter, retaining only one cysteine within the Ig-like domain. Mutations R435C and R471C in the Ig-like domain are linked to progeroid syndromes, fatal disorders characterized by premature aging. Here, we elucidate a pathogenic mechanism driven by aberrant disulfide cross-linking. We found that the R435C mutation, but not R471C, facilitates successive disulfide bond formation between Ig-like domains in vitro using purified recombinant proteins, causing nuclear deformation in lamin C-overexpressing cells. In lamin A-overexpressing cells, both R435C and R471C mutations induce additional intermolecular disulfide bonds involving the lamin A-specific cysteine residues in the C-terminal tail. Importantly, we demonstrate that glutathione and its precursor, N-acetyl cysteine, can disrupt these aberrant bonds. Using Caenorhabditis elegans as an in vivo model, we show that the orthologous cysteine mutation causes progeria phenotypes, which are suppressed by antioxidant treatment. These findings identify aberrant disulfide cross-linking as a key driver of progeria and suggest antioxidant therapies as a potential treatment strategy. Our study offers broader implications for vertebrate aging, suggesting that oxidative stress-mediated changes in lamin architecture are a conserved mechanism contributing to the loss of nuclear structural integrity and age-dependent nuclear aberration.