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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

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 5

Antisenescence effect of JH chemicals on normal aged cells.

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Antisenescence effect of JH chemicals on normal aged cells.
(A) Nuclear ...
(A) Nuclear deformation of aged fibroblasts was ameliorated by JH4. Normal cells obtained from 9-year-old (N9) and 81-year-old (N81) subjects were incubated with JH4 (5 μM) for 48 hours and stained with anti–lamin A/C Ab (green). DAPI was used for DNA staining. Scale bars: 10 μm. (B) JH4 could induce cell proliferation in aged fibroblasts. After seeding 7.5 × 104 cells per well, cells were maintained for a maximum of 6 days with the indicated JH chemicals (5 μM). Cell numbers were calculated every 48 hours. The slow proliferation of cells from N81 compared with that of cells from N9 (Figure 4B) was completely rescued by JH4 treatment. *P = 0.013. The P value was determined by Student’s t test for analysis of statistical significance between 2 groups. (C) JH4 suppressed senescence of N81 fibroblasts. An SA–β-gal assay was performed on cells from N81 after treatment with the indicated chemicals (5 μM) for 48 hours. Original magnification, ×40. (D) JH4 induced H3K9Me3 expression in normal aged cells. Immunofluorescence for H3K9Me3 (green) was performed in N9 and N81 cells under treatment with the indicated chemicals (5 μM) for 48 hours. Scale bars: 10 μm. (E) JH4 suppressed DCR2 and p16INK4A in normal human cells. Reverse transcriptase-PCR (RT-PCR) analysis of the indicated genes was performed in normal cell lines (N9, N29, and N81) after treatment with JH4 for 48 hours.
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