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Interruption of progerin–lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype
Su-Jin Lee, … , Gyu Yong Song, Bum-Joon Park
Su-Jin Lee, … , Gyu Yong Song, Bum-Joon Park
Published September 12, 2016
Citation Information: J Clin Invest. 2016;126(10):3879-3893. https://doi.org/10.1172/JCI84164.
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Research Article Aging Article has an altmetric score of 8

Interruption of progerin–lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype

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Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin–lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated β-gal (SA–β-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin–lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging.

Authors

Su-Jin Lee, Youn-Sang Jung, Min-Ho Yoon, So-mi Kang, Ah-Young Oh, Jee-Hyun Lee, So-Young Jun, Tae-Gyun Woo, Ho-Young Chun, Sang Kyum Kim, Kyu Jin Chung, Ho-Young Lee, Kyeong Lee, Guanghai Jin, Min-Kyun Na, Nam Chul Ha, Clea Bárcena, José M.P. Freije, Carlos López-Otín, Gyu Yong Song, Bum-Joon Park

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Figure 4

Antisenescence effect of the JH chemicals on HGPS cells.

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Antisenescence effect of the JH chemicals on HGPS cells.
(A) JH chemical...
(A) JH chemical overcame the growth suppression of HGPS cells. After seeding at 1 × 104 cells per well, cell proliferation was determined by cell counting every 48 hours for 6 days. The experiment was performed in triplicate. *P = 0.01, **P = 0.016. P values were determined by Student’s t test. (B) Cell proliferation assay of normal cells obtained from a 9-year-old person (N9) under the same condition as above. JH4 could induce proliferation of normal cells, particularly at late time points (between 4 and 6 days). (C) Induction of Ki-67 by JH4 in HGPS cells. Three types of HGPS cells were incubated with JH4 for 48 hours and stained with Ki-67 Ab (red). Scale bars: 10 μm. (D) JH chemicals suppressed SA–β-gal expression in HGPS cells. SA–β-gal assay of HGPS cells incubated with JH chemicals (5 μM, for 48 hours). The same result was obtained for other HGPS cells (Supplemental Figure 7A). Original magnification, ×40. (E) JH4 suppressed the half-life of progerin. Pulse-chase analysis using the de novo synthesis inhibitor cycloheximide (CHX) showed a rapid reduction of progerin by treatment with JH4. Cells, transfected with GFP-LMNA or GFP-progerin vectors, were incubated with 10 μM CHX for the indicated durations, with or without 5 μM JH4. (F) The proteasome inhibitor ALLN blocked progerin downregulation by JH4. (G) JH chemicals induced H3K9Me3 in HGPS cells. Cells, incubated with the indicated chemicals (5 μM) for 48 hours, were fixed with 100% Me-OH and stained with anti-H3K9Me9 Ab (green). DAPI was used for DNA staining (blue). Scale bars: 10 μm. Con, control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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