Accumulation of the Inner Nuclear Envelope Protein Sun1 Is Pathogenic in Progeric and Dystrophic Laminopathies

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• 作者：Chia-Yen Chen¹ ; ⁸ ; Ya-Hui Chi⁵ ; ⁸ ; ^{ychi@nhri.org.tw} ; Rafidah  ; Abdul Mutalif⁶ ; ⁸ ; Matthew  ; F. Starost² ; Timothy  ; G. Myers³ ; Stasia  ; A. Anderson⁴ ; Colin  ; L. Stewart⁶ ; ⁷ ; Kuan-Teh Jeang¹ ; ^{kjeang@nih.gov}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：27 April, 2012
• 卷：149
• 期：3
• 页码：565-577
• 文件大小：2355 K

摘要

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lass="h3">Summary

Human LMNA gene mutations result in laminopathies that include Emery-Dreifuss muscular dystrophy (AD-EDMD) and Hutchinson-Gilford progeria, the premature aging syndrome (HGPS). The Lmna null (Lmna^{鈭?鈭?/sup>}) and progeroid Lmna螖9 mutant mice are models for AD-EDMD and HGPS, respectively. Both animals develop severe tissue pathologies with abbreviated life spans. Like HGPS cells, Lmna^{鈭?鈭?/sup>} and Lmna螖9 fibroblasts have typically misshapen nuclei. Unexpectedly, Lmna^{鈭?鈭?/sup>} or Lmna螖9 mice that are also deficient for the inner nuclear membrane protein Sun1 show markedly reduced tissue pathologies and enhanced longevity. Concordantly, reduction of SUN1 overaccumulation in LMNA mutant fibroblasts and in cells derived from HGPS patients corrected nuclear defects and cellular senescence. Collectively, these findings implicate Sun1 protein accumulation as a common pathogenic event in Lmna^{鈭?鈭?/sup>}, Lmna螖9, and HGPS disorders.