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.

Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity

“…In a similar manner, proteasome inhibitor MG132 enhanced proliferation and decreased cellular senescence by promoting progerin degradation (Harhouri et al, ). Finally, treatment with the chemical JH4 ameliorated nuclear defects and prevented premature senescence by interfering with the harmful interaction between progerin and lamin A (Lee et al, ). Alternative strategies aimed to repair downstream effects of progerin have been proposed as well; treatment with methylene blue rescued not only nuclear morphology and heterochromatin loss but also mitochondrial function (Xiong et al, ), while administration of the ROCK inhibitor Y‐27632 ameliorated nuclear morphology defects and DNA double‐strand breaks along with decreased ROS levels and improvement of mitochondrial function (Kang et al, ).…”

Phosphorylated Lamin A/C in the nuclear interior binds active enhancers associated with abnormal transcription in progeria

“…In Hutchinson-Gilford progeria, the presence of the mutant LMNA protein is thought to alter the normal functions of wild-type LMNA (Lee et al, 2016). We therefore investigated the possibility that altered pS22-LMNA binding to enhancers contributed to gene expression changes in progeria.…”

“…In addition, the C-terminus in progerin exhibits reduced DNA and chromatin binding affinity in vitro (Bruston et al, 2010). Because the functional unit of LMNA is a dimer, the progeria mutations have been postulated to function as dominant negative alleles, producing progerin that may disrupt the normal functions of wild-type LMNA (Gordon et al, 2014;Lee et al, 2016). For example, LMNA's interactions with LADs are disrupted in progeria-patient fibroblasts 95 (McCord et al, 2012).…”

JH‐4 reduces HMGB1‐mediated septic responses and improves survival rate in septic mice

“…7 This late appearance of circulating HMGB1 precedes and parallels the onset of animal lethality from endotoxemia or sepsis and distinguishes it from TNF-α and other early proinflammatory cytokines. 12 However, to the best of our knowledge, the effects of JH-4 on HMGB1-mediated septic responses have not yet been studied. [8][9][10][11] As part of our ongoing research on the identification of novel lead compounds against Hutchinson-Gilford progeria syndrome (HGPS), we recently reported that JH-4, a synthesized decursin derivative, exhibits strong anti-HGPS activity by efficiently blocking progerin-lamin A/C binding.…”