ArticleProceedings of the National Academy of Sciences of the United States of America2019
Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Pooled it
- The nucleus as a mechanobiological hub in muscle aging.Nucleus (Austin, Tex.) · 2026Review
- Abnormal nuclear morphology in vivo in mouse hair follicle fibroblasts expressing progerin.Biochemical and biophysical research communications · 2026Article
- Age-related decline in nuclear envelope LINC complex drives neuronal aging via axon initial segment dysfunction.EMBO reports · 2026Article
- Farnesylated prelamin A induces fibroblast polarity defects in premature aging disorders by inhibiting nesprin-2-SUN2 LINC complex function.Journal of cell science · 2026Article
- Progerin cross-linking stiffens the nucleus and impairs mechanosensation in Hutchinson-Gilford progeria syndrome.Journal of cell science · 2026Article
- LAV-BPIFB4 reverses progeria-associated cardiac aging by restoring diastolic function and reducing senescence.International journal of biological sciences · 2026Article
- Protein farnesylation: from molecular mechanisms to therapeutic targeting in cancer, aging, and beyond.Frontiers in pharmacology · 2026Review
- Elevated SUN1 promotes migratory cell polarity defects through mechanically coupling microtubules to the nuclear lamina.Communications biology · 2025Article
- Nuclear envelope components in vascular mechanotransduction: emerging roles in vascular health and disease.Nucleus (Austin, Tex.) · 2025Review
- Increased substrate stiffness disrupts nuclear-cytoskeletal mechanical coupling in senescent cells.Materials today. Bio · 2025Article
- Molecular models of the sperm head-tail coupling apparatus.Journal of cell science · 2025Review
- Attenuated Nuclear Tension Regulates Progerin-Induced Mechanosensitive Nuclear Wrinkling and Chromatin Remodeling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Migratory responses in enucleated cells: The forces driving the locomotion movement of unicellular organisms.PNAS nexus · 2025Article
- TRF2 interaction with nuclear envelope is required for cell polarization and metastasis in triple negative breast cancer.Cell death & disease · 2025Article
- Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression.Biomarker research · 2025Review
- Remodeling of cytoskeleton, chromatin, and gene expression during mechanical rejuvenation of aged human dermal fibroblasts.Molecular biology of the cell · 2025Article
- VPS4B orchestrates response to nuclear envelope stress by regulating ESCRT-III dynamics in glioblastoma.Nucleus (Austin, Tex.) · 2024Article
- Progerin forms an abnormal meshwork and has a dominant-negative effect on the nuclear lamina.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Prrx1-driven LINC complex disruption in vivo reduces osteoid deposition but not bone quality after voluntary wheel running.bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
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