Progerin forms an abnormal meshwork and has a dominant- negative effect on the nuclear lamina

• 成果类型: Article
• 署名作者: Kim, Paul H.; Kim, Joonyoung R.; Tu, Yiping; Jung, Hyesoo; Jeong, J. Y. Brian; Tran, Anh P.; Presnell, Ashley; Young, Stephen G.; Fong, Loren G.
• 署名单位: University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13253
• DOI: 10.1073/pnas.2406946121
• 发表日期: 2024-07-02
• 关键词: disease phenotypes; syndrome alters; mouse model; prelamin-a; farnesylation; envelope; localization; ORGANIZATION; fibroblasts; mutations

摘要

nuclear membrane (NM) ruptures and blebs, but the mechanisms are unclear. We susHigh- resolution microscopy of smooth muscle cells (SMCs) revealed that lamin A and lamin B1 form independent meshworks with uniformly spaced openings (-0.085 mu m2). The expression of progerin in SMCs resulted in the formation of an irregular meshwork with clusters of large openings (up to 1.4 mu m2). The expression of progerin acted in a dominant- negative fashion to disrupt the morphology of the endogenous lamin B1 meshwork, triggering irregularities and large openings that closely resembled the irregularities and openings in the progerin meshwork. These abnormal meshworks were strongly associated with NM ruptures and blebs. Of note, the progerin meshwork was markedly abnormal in nuclear blebs that were deficient in lamin B1 (-50% of all blebs). That observation suggested that higher levels of lamin B1 expression might normalize the progerin meshwork and prevent NM ruptures and blebs. Indeed, increased lamin B1 expression reversed the morphological abnormalities in the progerin meshwork and markedly reduced the frequency of NM ruptures and blebs. Thus, progerin expression disrupts the overall structure of the nuclear lamina, but that effect-along with NM ruptures and blebs-can be abrogated by increased lamin B1 expression.