Increased expression of LAP2β eliminates nuclear membrane ruptures in nuclear lamin-deficient neurons and fibroblasts.

Abstract

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 LAP2β, a chromatin-binding inner NM protein, in fibroblasts with NM ruptures. Here, we explored the apparent link between LAP2β and NM ruptures in nuclear lamin-deficient neurons and fibroblasts, and we tested whether manipulating LAP2β expression levels would alter NM rupture frequency. In cortical plate neurons of lamin B1-deficient embryos, we observed a strong correlation between low LAP2β levels and NM ruptures. We also found low LAP2β levels and frequent NM ruptures in neurons of cultured Lmnb1-/- neurospheres. Reducing LAP2β expression in Lmnb1-/- neurons with an siRNA markedly increased the NM rupture frequency (without affecting NM rupture duration), whereas increased LAP2β expression eliminated NM ruptures and reduced DNA damage. Consistent findings were observed in nuclear lamin-deficient fibroblasts. Reduced LAP2β expression increased NM ruptures, whereas increased LAP2β expression virtually abolished NM ruptures. Increased LAP2β expression nearly abolished NM ruptures in cells subjected to mechanical stress (an intervention that increases NM ruptures). Our studies showed that increasing LAP2β expression bolsters NM integrity in nuclear lamin-deficient cells and markedly reduces NM rupture frequency.

• Authors: Natalie Y Chen, Paul H Kim, Yiping Tu, Ye Yang, Patrick J Heizer, Stephen G Young, Loren G Fong
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 25 (06 22 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34161290 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA-Binding Proteins
• Lamin Type A
• Lamin Type B
• Membrane Proteins
• lamin B1
• lamin B2
• lamina-associated polypeptide 2

Topics

• Animals
• Cell Death
• Cell Differentiation
• Cerebral Cortex (pathology)
• DNA Damage
• DNA-Binding Proteins (metabolism)
• Embryo, Mammalian (metabolism)
• Fibroblasts (metabolism)
• Lamin Type A (deficiency, metabolism)
• Lamin Type B (deficiency, metabolism)
• Membrane Proteins (metabolism)
• Mice, Knockout
• Neurons (metabolism)
• Nuclear Envelope (metabolism)
• Organ Specificity