Cell
Volume 149, Issue 3, 27 April 2012, Pages 565-577
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Article
Accumulation of the Inner Nuclear Envelope Protein Sun1 Is Pathogenic in Progeric and Dystrophic Laminopathies

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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−/−) and progeroid LmnaΔ9 mutant mice are models for AD-EDMD and HGPS, respectively. Both animals develop severe tissue pathologies with abbreviated life spans. Like HGPS cells, Lmna−/− and LmnaΔ9 fibroblasts have typically misshapen nuclei. Unexpectedly, Lmna−/− or LmnaΔ9 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−/−, LmnaΔ9, and HGPS disorders.

Highlights

▸ Premature death of progeric and dystrophic mice is ameliorated by removal of Sun1 ▸ LMNA mutations cause Sun1 overaccumulation in the Golgi ▸ Sun1 overaccumulation in the Golgi is pathogenic ▸ Cellular senescence of HGPS fibroblasts is corrected by depletion of SUN1

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These authors contributed equally to this work