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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 8

Lifespan extension in progerin-expressed mice.

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Lifespan extension in progerin-expressed mice.
(A) Representative photog...
(A) Representative photograph of 40-week-old Lmna+/G609G control or JH4-treated mice. (B) BW of 40-week-old Lmna+/G609G control and JH4-treated mice. (C) In vivo effect of JH4 on binding between progerin and lamin A/C. Lmna+/G609G mice that received a single injection of JH4 (10 mg/kg) were sacrificed for IP analysis of liver and kidney. After 6 hours, JH4 could disrupt the interaction of progerin and lamin A. After 24 hours, dissociation of progerin and lamin A was detected in kidney. Extracted proteins were immunoprecipitated with progerin Ab, and the precipitated proteins were subjected to Western blotting with anti–lamin A/C or anti-progerin Ab. (D) Detection of JH4 in liver. Biotin-JH4 was injected into Lmna+/G609G mice, and liver lysates were reacted with streptavidin beads. Precipitated proteins were analyzed by Western blotting. (E) Kaplan-Meier survival plots for LmnaG609G/G609G mice treated with JH4 (n = 13) or with vehicle alone (n = 11). (F) Kaplan-Meier survival plots for Lmna+/G609G mice treated with vehicle (n = 6) or JH4 (n = 10). (G) Extension of lifespan by high-dose injection of JH4. A dose of 20 mg/kg JH4 could extend lifespan by as much as 26 weeks. (B and E–G) P values were determined by Student’s t test.
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