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

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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 126 Issue 10 Pg. 3879-3893 (10 03 2016) ISSN: 1558-8238 [Electronic] United States
• PMID: 27617860 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(3-pyridyl)acrylic acid 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano(3,2-g)chromen-7-yl ester
• Acrylates
• Coumarins
• Lamin Type A
• Protein Isoforms
• prelamin A

Topics

• Acrylates (chemistry, pharmacology)
• Animals
• Cellular Senescence
• Coumarins (chemistry, pharmacology)
• Drug Evaluation, Preclinical
• Endoplasmic Reticulum (drug effects, metabolism)
• Female
• Gene Expression (drug effects)
• HEK293 Cells
• Humans
• Lamin Type A (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Phenotype
• Progeria (drug therapy, metabolism)
• Protein Binding
• Protein Isoforms (metabolism)
• Protein Transport (drug effects)