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Increased expression of LAP2ß eliminates nuclear membrane ruptures in nuclear lamin-deficient neurons and fibroblasts.
Chen, Natalie Y; Kim, Paul H; Tu, Yiping; Yang, Ye; Heizer, Patrick J; Young, Stephen G; Fong, Loren G.
Afiliación
  • Chen NY; Department of Medicine, University of California, Los Angeles, CA 90095.
  • Kim PH; Department of Medicine, University of California, Los Angeles, CA 90095.
  • Tu Y; Department of Medicine, University of California, Los Angeles, CA 90095.
  • Yang Y; Department of Medicine, University of California, Los Angeles, CA 90095.
  • Heizer PJ; Department of Medicine, University of California, Los Angeles, CA 90095.
  • Young SG; Department of Medicine, University of California, Los Angeles, CA 90095; sgyoung@mednet.ucla.edu lfong@mednet.ucla.edu.
  • Fong LG; Department of Human Genetics, University of California, Los Angeles, CA 90095.
Proc Natl Acad Sci U S A ; 118(25)2021 06 22.
Article en En | MEDLINE | ID: mdl-34161290
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 LAP2ß, a chromatin-binding inner NM protein, in fibroblasts with NM ruptures. Here, we explored the apparent link between LAP2ß and NM ruptures in nuclear lamin-deficient neurons and fibroblasts, and we tested whether manipulating LAP2ß expression levels would alter NM rupture frequency. In cortical plate neurons of lamin B1-deficient embryos, we observed a strong correlation between low LAP2ß levels and NM ruptures. We also found low LAP2ß levels and frequent NM ruptures in neurons of cultured Lmnb1-/- neurospheres. Reducing LAP2ß expression in Lmnb1-/- neurons with an siRNA markedly increased the NM rupture frequency (without affecting NM rupture duration), whereas increased LAP2ß expression eliminated NM ruptures and reduced DNA damage. Consistent findings were observed in nuclear lamin-deficient fibroblasts. Reduced LAP2ß expression increased NM ruptures, whereas increased LAP2ß expression virtually abolished NM ruptures. Increased LAP2ß expression nearly abolished NM ruptures in cells subjected to mechanical stress (an intervention that increases NM ruptures). Our studies showed that increasing LAP2ß expression bolsters NM integrity in nuclear lamin-deficient cells and markedly reduces NM rupture frequency.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Lamina Tipo B / Proteínas de Unión al ADN / Fibroblastos / Proteínas de la Membrana / Neuronas / Membrana Nuclear Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Lamina Tipo B / Proteínas de Unión al ADN / Fibroblastos / Proteínas de la Membrana / Neuronas / Membrana Nuclear Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos