Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 10, Pages 3879-3893Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI84164
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Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [NRF-2013R1A1A2010008, 2009-0093815, 2014R1A2A2A01005455, NRF-2013R1A1A2063077]
- Progeria Research Foundation
- Ministerio de Economia y Competitividad of Spain
- Red Tematica de investigacion cooperativa en cancer -Institute de Salud
- Obra Social Cajastur-Asturias
- National Research Foundation of Korea [2014R1A2A2A01005455, 2013R1A1A2010008] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 beta-gal (SA-beta-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 Lmna(G689G/G669G)-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.
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