Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging

Wakam Chang, Yuexia Wang, G. W. Gant Luxton, Cecilia Östlund, Howard J. Worman, Gregg G. Gundersen

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Studies of the accelerated aging disorder Hutchinson–Gilford progeria syndrome (HGPS) can potentially reveal cellular defects associated with physiological aging. HGPS results from expression and abnormal nuclear envelope association of a farnesylated, truncated variant of prelamin A called “progerin.” We surveyed the diffusional mobilities of nuclear membrane proteins to identify proximal effects of progerin expression. The mobilities of three proteins—SUN2, nesprin-2G, and emerin—were reduced in fibroblasts from children with HGPS compared with those in normal fibroblasts. These proteins function together in nuclear movement and centrosome orientation in fibroblasts polarizing for migration. Both processes were impaired in fibroblasts from children with HGPS and in NIH 3T3 fibroblasts expressing progerin, but were restored by inhibiting protein farnesylation. Progerin affected both the coupling of the nucleus to actin cables and the oriented flow of the cables necessary for nuclear movement and centrosome orientation. Progerin overexpression increased levels of SUN1, which couples the nucleus to microtubules through nesprin-2G and dynein, and microtubule association with the nucleus. Reducing microtubule-nuclear connections through SUN1 depletion or dynein inhibition rescued the polarity defects. Nuclear movement and centrosome orientation were also defective in fibroblasts from normal individuals over 60 y, and both defects were rescued by reducing the increased level of SUN1 in these cells or inhibiting dynein. Our results identify imbalanced nuclear engagement of the cytoskeleton (microtubules: high; actin filaments: low) as the basis for intrinsic cell polarity defects in HGPS and physiological aging and suggest that rebalancing the connections can ameliorate the defects.

Original languageEnglish (US)
Pages (from-to)3578-3583
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number9
DOIs
StatePublished - Feb 26 2019

Bibliographical note

Funding Information:
This research was supported by NIH Grants GM099481 (to G.G.G.) and AR068636 (to G.G.G. and H.J.W.).

Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.

Keywords

  • Centrosome orientation
  • Hutchinson–Gilford progeria syndrome
  • LINC complex
  • Nuclear movement
  • SUN proteins

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