| First Author | Chen NY | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 25 | PubMed ID | 34161290 |
| Mgi Jnum | J:307035 | Mgi Id | MGI:6718751 |
| Doi | 10.1073/pnas.2107770118 | Citation | Chen NY, et al. (2021) Increased expression of LAP2beta eliminates nuclear membrane ruptures in nuclear lamin-deficient neurons and fibroblasts. Proc Natl Acad Sci U S A 118(25):e2107770118 |
| abstractText | Defects or deficiencies in nuclear lamins cause pathology in many cell types, and recent studies have implicated nuclear membrane (NM) ruptures as a cause of cell toxicity. We previously observed NM ruptures and progressive cell death in the developing brain of lamin B1-deficient mouse embryos. We also observed frequent NM ruptures and DNA damage in nuclear lamin-deficient fibroblasts. Factors modulating susceptibility to NM ruptures remain unclear, but we noted low levels of LAP2beta, a chromatin-binding inner NM protein, in fibroblasts with NM ruptures. Here, we explored the apparent link between LAP2beta and NM ruptures in nuclear lamin-deficient neurons and fibroblasts, and we tested whether manipulating LAP2beta expression levels would alter NM rupture frequency. In cortical plate neurons of lamin B1-deficient embryos, we observed a strong correlation between low LAP2beta levels and NM ruptures. We also found low LAP2beta levels and frequent NM ruptures in neurons of cultured Lmnb1 (-/-) neurospheres. Reducing LAP2beta expression in Lmnb1 (-/-) neurons with an siRNA markedly increased the NM rupture frequency (without affecting NM rupture duration), whereas increased LAP2beta expression eliminated NM ruptures and reduced DNA damage. Consistent findings were observed in nuclear lamin-deficient fibroblasts. Reduced LAP2beta expression increased NM ruptures, whereas increased LAP2beta expression virtually abolished NM ruptures. Increased LAP2beta expression nearly abolished NM ruptures in cells subjected to mechanical stress (an intervention that increases NM ruptures). Our studies showed that increasing LAP2beta expression bolsters NM integrity in nuclear lamin-deficient cells and markedly reduces NM rupture frequency. |
