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Research Paper
Endothelial and systemic upregulation of miR-34a-5p fine-tunes senescence in progeria
Relevance score: 20.562326Christina Manakanatas, Santhosh Kumar Ghadge, Azra Agic, Fatih Sarigol, Petra Fichtinger, Irmgard Fischer, Roland Foisner, Selma Osmanagic-Myers
Keywords: Hutchinson-Gilford progeria syndrome, cardiovascular disease, endothelial senescence, senescence-associated micro RNAs
Published in Aging on January 12, 2022
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Editorial Volume 13, Issue 12 pp 15697-15698
The pursuit of therapy for progeria
Relevance score: 27.00524Saurabh Saxena, Dhananjay Shukla
Keywords: aging, Hutchinson-Gilford Progeria Syndrome, therapeutics
Published in Aging on June 27, 2021
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Editorial Volume 12, Issue 6 pp 4682-4684
Nuclear protein export pathway in aging therapeutics
Relevance score: 19.301662Bulmaro Cisneros, Ian García-Aguirre
Keywords: aging, Hutchinson-Gilford progeria syndrome, progerin, nuclear protein export, CRM1, selinexor
Published in Aging on March 19, 2020
Schematic model showing phenotypic rescue of HGPS cells through pharmacological modulation of CRM1-mediated nuclear export signaling. (Normal) CRM1 in complex with Ran-GTP drives the export of proteins from the nucleus (Nu) to the cytoplasm (Cyt) across the nuclear pore complex (NPC), via recognition of a nuclear export signal on the cargo molecules, maintaining thereby a balanced partition of proteins between these cellular compartments. INM, inner nuclear membrane; ONM, outer nuclear membrane; ER endoplasmic reticulum. (HGPS) HGPS cells exhibit exacerbated nuclear protein export activity due to progerin-driven CRM1 overexpression, which in turn provokes the appearance of cellular marks of aging, including mitochondrial dysfunction, the loss of heterochromatin, decreased lamin B1 levels, nucleolar expansion and aberrant nuclear morphology. (HGPS+LMB) Mitigation of CRM1 activity by treatment of HGPS cells with specific CRM1 inhibitor (LMB) alleviates all aforementioned aging marks, by restoring proper nuclear-cytoplasmic distribution of proteins.
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Research Paper Volume 10, Issue 11 pp 3148-3160
BK channel overexpression on plasma membrane of fibroblasts from Hutchinson-Gilford progeria syndrome
Relevance score: 14.0455675Isabella Zironi, Entelë Gavoçi, Giovanna Lattanzi, Angela Virelli, Fabrizio Amorini, Daniel Remondini, Gastone Castellani
Keywords: Hutchinson-Gilford Progeria Syndrome (HGPS), gene LMNA, aging, patch clamp, membrane channels, K current +, cellular proliferation
Published in Aging on November 6, 2018
Outward currents patch-clamp recorded in whole-cell configuration. (A) Representative examples of current traces recorded in hDF obtained from a young donor, an elderly, and a patient affected by HGPS. Current traces recorded after 100 nM IbTx application and a graphical representation of the pulse protocol (holding potential at 0 mV) are also shown. (B) Average ± SEM of current-voltage relationships (I–V) recorded in hDF obtained from healthy donors (Young, n=83; Elderly, n=16) and patients affected by HGPS (n=80). (C) Average ± SEM of current-voltage relationships (I–V) recorded in hDF obtained from young donors and patients affected by HGPS treated by 100 nM IbTx (n=6) and 10 mM TEA (n=4). Young vs. HGPS: *p<0.05; **p<0.01; Young vs. Elderly: #p<0.05; ##p<0.001; ###p<0.0001.
Immunofluorescence detection for BKCa channels expressed on plasma membrane in fixed cells. (A) Fluorescence micrographs of isolated hDF obtained from young and HGPS donors incubated with an anti-BKCa α subunit primary antibody visualized by FITC-conjugated secondary antibody and acquired at 200× magnification. Scale bars: 100 μm. (B). Quantification of mean fluorescence intensity of anti-BKCa antibody-stained cells. The green fluorescence intensity values are obtained from 30 cells (A.U. ± SEM). Significant differences calculated according to the Student’s t-test (p<0.05) are indicated.
Immunofluorescence detection for BKCa channels expressed on plasma membrane in living cells. (A) Fluorescence and fluorescence/phase contrast merged micrographs of isolated hDF obtained from young, elderly and HGPS donors incubated with an anti-BKCa α subunit primary antibody visualized by the conjugated Alexa Fluor 350 fluorophore and acquired at 200× magnification. Scale bars: 100 μm. (B) Histogram showing the percentage of cells expressing a blue fluorescence intensity over a fixed threshold (% ± SEM). Significant differences calculated according to the Student’s t-test (p<0.05) are indicated.
Detection of calcium concentration by fluorescence in living cells. (A) Fluorescence and fluorescence/phase contrast merged micrographs of isolated hDF obtained from young, elderly and HGPS donors incubated with the cell-permeant Ca2+ indicator Fluo-4 AM (2 μM) and at 200× magnification. Scale bars: 100 μm. (B) Quantification of Mean and Max fluorescence intensity (A.U. ± SEM). Significant differences calculated according to the Student’s t-test (p<0.05) are indicated.
Proliferation and adhesion rates without and with the BKCa inhibitor IbTx. (A) Average number of hDF obtained from young healthy donors and patients affected by HGPS estimated at 48, 72 and 96 hours from seeding and normalized at 24 h (fold-change ± SEM). Healthy and HGPS hDF were allowed to proliferate untreated (Young n=54; HGPS n=36) and treated by 100 nM IbTx (Young n=53; HGPS n=36). Young vs. HGPS: **p<0.001; ****p<5×10-7; Young vs. Young + IbTx: §p<0.01; HGPS vs. HGPS + IbTx: #p<0.01; ###p<0.0001. (B) Average percentage ± SEM of adherent hDF cells counted 2 h after seeding, treated (Young n=35, HGPS n=22) and untreated by 100 nM IbTx (Young n=40, HGPS n=24); image legend is the same as Figure A.
Percentage of senescent cells. (A) Representative micrographs of isolated hDF obtained from young, elderly and HGPS donors. Cells with blue staining indicated positive for SA β-galactosidase activity. Images acquired in transmission light bright field at 400× magnification. Scale bar: 10 μm. (B) The percentages of positive hDF from Young, Elderly and HGPS groups are reported in the graph as mean value of three independent staining (% ± STD). Significant differences calculated according to the Student’s t-test (p<0.05) are indicated.
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Research Paper Volume 8, Issue 2 pp 366-381
Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase
Relevance score: 19.664267Olga Moiseeva, Stéphane Lopes-Paciencia, Geneviève Huot, Frédéric Lessard, Gerardo Ferbeyre
Keywords: lamin A, cyclin dependent kinases, senescence, liquid droplets, Hutchinson-Gilford progeria syndrome
Published in Aging on February 21, 2016
(A) Schematic representation of prelamin A alleles cloned into retroviral vectors and used in this study. FS= farnesylation site. Note the ZMPSTE24 cleavage site (arrow) that is absent in progerin. (B-C) Immunofluorescence for lamin A/C of U-2 OS cell expressing progerin or progerin CS with wild type S22 or mutations S22A or S22D. Cells were fixed 5 days after infection. The percent and standard deviation (S.D) of cells having each pattern is indicated at the bottom right of each panel. (D) Immunofluorescence images of U-2 OS cell coexpressing progerin CS fused with Red fluorescent protein (RFP) and prelamin A fused with GFP. Magnification = 10 μm.
(A) Immunoblots for phosphorylated lamin A at serines 22 and 392 in U-2 OS cells expressing progerin (Prog) or progerin CS (ProgCS). (B) Immunofluorescence for phosphoserine 22 lamin A (p-S22Lam) in U-2 OS cells expressing progerin or progerin CS. Magnification = 10 μm. (C) Immunoblot for phosphoserine 22 lamin A in U-2 OS cells expressing progerin and treated with 3 μM FTI-277 or vehicle. (D) Immunofluorescence for phosphoserine 22 lamin A in cells expressing progerin and treated with 3 μM FTI-277 or vehicle. (E) Colony assays of U2-OS cells expressing the indicated vectors and treated with 3 μM FTI-277 or vehicle. (F) Quantification of the colony assay in (E).
(A) Immunofluorescence with anti-lamin A/C and anti-serine 22 phosphorylated lamin A in U-2 OS cells expressing the indicated proteins. (B) Phosphoserine 22 lamin A immunoblots in U-2 OS cells expressing the indicated proteins. (C) Immunofluorescence with anti-lamin A antibody in U-2 OS cells expressing Progerin R50P CS and treated with 1% hexanediol or vehicle. (D) Growth analysis of U-2 OS cells expressing the indicated proteins. (E) Anti-MCM6 and anti-progerin immunoblots in U-2 OS cells expressing the indicated proteins.
(A) Immunofluorescence with anti-lamin A/C (LamA/C, green) and antibodies against indicated kinases (red) in U-2 OS cells expressing R50P mutant of non-farnesylated progerin (R50PprogerinCS). (B) Phosphoserine 22 lamin A immunoblots in U-2 OS cells expressing non-farnesylated progerin (ProgerinCS) treated with 100 nM flavopiridol or vehicle for 2 days. (C) Lamin A and phosphoserine 22 lamin A immunoblots and phosphoserine 22 lamin A/lamin A (p-S22 LamA) quantified immunoblots and expression ratio estimation of phosphoserine 22 lamin A/lamin A (pS22/LamA) in U-2 OS cells expressing mature lamin A treated with 1 μM PD0332991 (PD) or 100 nM flavopiridol (Flav) or vehicle for 2 days. (D) Lamin A and CDK6 immunoblots in U-2 OS cells expressing shCDK6s or a control shRNA (V). (E) Immunofluorescence for lamin A/C and CDK6 in cells as in (D). Scale bar: 10 μm.
(A) Immunoblots for lamin A/C and phosphoserine 22 lamin A in fibroblasts from HGPS patients. (B) Normalizing phosphoserine 22 lamin A levels to progerin levels using the data in (A). (C) Immunofluorescence for lamin A/C in BJ young fibroblasts and HGPS fibroblasts after treatment with 3 μM FTI-277 or vehicle. (D) Immunofluorescence for lamin A/C and phospho serine 22 lamin A in HGPS fibroblasts after treatment with 3 μM FTI-277 or vehicle. (E) Immunofluorescence for phosphoserine 22 lamin A in HGPS fibroblasts after treatment with 3 μM FTI-277 and/or 60 nM flavopiridol or 1μM PD0332991 (PD).
(A) Population doublings calculated after serial passage of the cells starting at population doubling 9 and treated with vehicle or 60 nM flavopiridol for the indicated amount of days. (B) Immunoblots in cells as in (A) for the indicated proteins.
This phase separation can make soluble lamin A available for nucleoplasmic functions and allows lamin A turnover, regulating the overall size and stiffness of the envelope. Progerin is not defarnesylated and is resistant to phosphorylation at serine 22, compromising its solubilization, nucleoplasmic functions and turnover. FTI-277 or the mutation of the farnesylation site (CS) partially correct the defects in progerin but the solid to liquid transition is defective and intranuclear progerin forms mostly fibrous rods. New treatments are required for a full normalization of lamin A in progeria.
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Research Paper Volume 6, Issue 12 pp 1049-1063
Progerin expression disrupts critical adult stem cell functions involved in tissue repair
Relevance score: 22.336918Laurin Marie Pacheco, Lourdes Adriana Gomez, Janice Dias, Noel M Ziebarth, Guy A Howard, Paul C Schiller
Keywords: aging, progerin, HGPS, Hutchinson-Gilford Progeria Syndrome, Progeria, MSC
Published in Aging on December 21, 2014
MIAMI cells stably expressing GFP-lamin A and GFP-progerin transgenes demonstrate nuclear abnormalities that can be ameliorated by FTI. (A) Immunofluorescent images of GFP-lamin A and GFP-progerin MIAMI cells. MIAMI cells collected from a 20-year old individual were retrovirally transduced with vectors containing GFP-lamin A and GFP-progerin transgenes, and a vector control. Cells were stained with antibody against Lamin A/C and immunofluorescently imaged to visualize Lamin A expression. (B) Representative image of MIAMI cell nuclei expressing lamin A only (left) or progerin (right). (C) Representative images of western blots probed with antibodies against Lamin A only, Progerin only, and GFP. Endogenous lamin A was used as a loading control. UT=Untransduced MIAMI cells, EV= Empty vector control, Lamin A=GFP-Lamin A transduced, Progerin=GFP-Progerin transduced. Vector control cells in panel C were not transduced with transgene expressing GFP. (D) Quantification by flow cytometry of GFP expression in control and transduced cell lines. (E) Progerin expression from a transgene significantly increases nuclear abnormalities in MIAMI cells, and FTI treatment ameliorates these effects. FTI treatment did not significantly affect GFP-lamin A MIAMI cells. Values are mean ± standard deviation (n≥3). *p<0.001, calculated by Student's t-test.
MIAMI cells can express endogenous progerin. (A) Endogenous progerin mRNA levels measured by qPCR in MIAMI cells collected from non-HGPS male donors of various ages (7-65 years). Progerin-transduced MIAMI cells collected from a 20-year-old donor (+) were used as a positive control. MIAMI cells collected from a 20 year old (−) were used as a negative control. (B) Using primer pairs to amplify both progerin and lamin A, qPCR results were run on an agarose gel to visualize amplification product length. Miami cells collected from a 65-year-old donor and progerin transduced MIAMI cells express both lamin A and progerin products. Values in Panel A are mean ± standard deviation (n≥3). *p<0.05, calculated by Student's t-test. P-values indicate significant difference between negative control, unless otherwise noted.
Progerin decreases self-renewal markers and leads to cytoplasmic accumulation of self-renewal transcription factors. (A) qPCR analysis of self-renewal markers that are normally expressed in MIAMI cells. Progerin expression significantly decreases Oct4, hTeRT, Notch2, and Hes5 mRNA expression. FTI treatment significantly increases mRNA expression of these self-renewal markers. Dotted line represents control, untreated lamin A-MIAMI cells set to 1. Asterisk over progerin-MIAMI cells signifies progerin-MIAMI cells significantly differently from untreated lamin A-MIAMI cells. Values are mean ± standard deviation (n≥3). *p<0.05, calculated by Student's t-test. (B) Immunofluorescent images of progerin and lamin A MIAMI cells demonstrate that progerin expression leads to Notch2 and Oct4 accumulation in the cytoplasm, which is normally localized to the nucleus in lamin A MIAMI cells.
Progerin expression decreases MIAMI cell proliferation. (A) Quantification of Ki67 immunofluorescent staining. At least 10 random fields per cell line were selected and cells were scored as positive or negative for Ki67 expression. Progerin expression significantly decreases Ki67 expression when compared to lamin A MIAMI cells in the same passage. (B) Immunofluorescent images of transgene and Ki67 expression, a marker of proliferation, in lamin A and progerin MIAMI cells. (C) Growth curve of untransduced MIAMI cells, vector control, lamin A, and progerin MIAMI cells. Progerin expression significantly decreases cell number at days 3, and 5 when compared to control cells. There were no significant differences between the control cell lines. Values are mean ± standard deviation (n≥3). *p<0.05, calculated by Student's t-test.
Progerin expression significantly decreases MIAMI cell migration. (A) GFP-lamin A MIAMI and GFP-progerin MIAMI cells were scraped at 0 hrs with a 2mL glass pipette tip. Scraped areas were imaged at 0, 24, 48, and 72 hours, with and without FTI, to monitor cellular migration. (B) Progerin expression significantly decreases migration at 24, 48, and 72 hours. FTI treatment significantly increases migration at 24, 48, and 72 hours when compared to untreated progerin MIAMI cells. (C) Lamin A and Progerin MIAMI cells were plated in MIAMI media containing no FBS in the upper chamber of a transwell. MIAMI media with FBS was placed in the bottom chamber. After 24 hours, cells remaining in the upper chamber were washed away, and cells that migrated to the bottom of the transwell were stained with DAPI and immunofluorescently imaged. Progerin expression significantly decreases migration through the transwell membrane. Values are mean ± standard deviation (n≥3). *p<0.05, calculated by Student's t-test.
Progerin expression significantly alters membrane stiffness when measured by atomic force microscopy. (A,D) Progerin expression significantly increases membrane stiffness in both cytoplasmic (A) and nuclear (D) regions when compared to control cell lines, while stiffness in cytoplasmic and nuclear regions are not significantly different between control cell lines. (B, E) FTI treatment significantly decreases membrane stiffness in cytoplasmic (B) and nuclear (E) regions in progerin-MIAMI cells when compared to untreated progerin-MIAMI cells, while stiffness in cytoplasmic and nuclear regions are not significantly different before and after FTI treatment in control cell lines. (C, F) FTI treatment significantly decreases membrane stiffness in cytoplasmic (C) and nuclear (F) regions in progerin-MIAMI cells to levels that are significantly less than treated control cell lines, while stiffness in cytoplasmic and nuclear regions are not significantly different between control cell lines after FTI treatment. Values are mean ± standard deviation (n≥3). *p<0.05, **p<0.01, calculated by Student's t-test.
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Review Volume 1, Issue 1 pp 28-37
Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A
Relevance score: 14.0455675Phillip R. Musich, Yue Zou
Keywords: Lamin A, Hutchinson-Gilford progeria syndrome, premature aging, Genome instability, DNA damage responses, XPA, DNA double strand breaks, DNA repair
Published in Aging on January 16, 2009
(A) Normal processing of prelamin A. (B) Processing of G608G mutation (C1824T) in HGPS cells. Underline LY (in black) in the deleted 50 AAs: Zmpste24 cleavage site
In response to DNA damage, two major cellular pathways, DNA damage checkpoints and DNA repair, are activated for maintaining genome integrity and stability.
Unlike the replication fork collapse induced by genotoxins, laminopathy-induced replication fork collapse may be characterized with a possible loss of PCNA at replication forks. The subsequent possible binding of XPA to the "naked" replication forks with DNA double-strand breaks (DSBs) blocks the access of DSB repair proteins to the damage sites. RFs stands for replication factors.