Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes.

Ray Kreienkamp,Susana Gonzalo,Monica Croke,Dale Dorsett,Adriana Dusso,Gonzalo Bedia-Diaz,Carsten Carlberg,Simona Graziano,Martin A Neumann

doi:10.18632/oncotarget.9065

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating incurable premature aging disease caused by accumulation of progerin, a toxic lamin A mutant protein. HGPS patient-derived cells exhibit nuclear morphological abnormalities, altered signaling pathways, genomic instability, and premature senescence. Here we uncover new molecular mechanisms contributing to cellular decline in progeria. We demonstrate that HGPS cells reduce expression of vitamin D receptor (VDR) and DNA repair factors BRCA1 and 53BP1 with progerin accumulation, and that reconstituting VDR signaling via 1α,25-dihydroxyvitamin D3 (1,25D) treatment improves HGPS phenotypes, including nuclear morphological abnormalities, DNA repair defects, and premature senescence. Importantly, we discovered that the 1,25D/VDR axis regulates LMNA gene expression, as well as expression of DNA repair factors. 1,25D dramatically reduces progerin production in HGPS cells, while stabilizing BRCA1 and 53BP1, two key factors for genome integrity. Vitamin D/VDR axis emerges as a new target for treatment of HGPS and potentially other lamin-related diseases exhibiting VDR deficiency and genomic instability. Because progerin expression increases with age, maintaining vitamin D/VDR signaling could keep the levels of progerin in check during physiological aging.

Highlights

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare but severe premature aging disease
Lamin A/C loss correlates with decreases in BRCA1, and to a lesser extent in 53BP1 levels, key factors in DNA repair by homologous recombination (HR) and non-homologous end joining (NHEJ) respectively, as previously observed in mouse fibroblasts and breast cancer cells [29]
Similar decreases in vitamin D receptor (VDR) and DNA repair factors were observed upon depletion of lamin A/C in human primary vascular smooth muscle cells (VSMC) (Figure 1B), a cell type susceptible to alterations in lamin A/C function [30, 31]

Summary

Introduction

HGPS is a rare but severe premature aging disease. Affected patients die in their teens from myocardial infarction or stroke as a result of rapidly progressive atherosclerosis [1,2,3]. Most cases are caused by a G608G(GGC > GGT) single-base mutation within exon 11 of the LMNA gene [4, 5], which codes for lamin A/C via alternative splicing. This mutation activates a cryptic splice site that prevents proper processing of prelamin A to mature lamin A and produces a permanently farnesylated and carboxymethylated toxic product called “progerin”. These post-translational progerin modifications seem to play a major role in the pathophysiology of disease [69]. Progerin disrupts the nuclear lamina, a compartment essential for nuclear structure and function, provoking an array of cellular aberrations, including nuclear morphological abnormalities, increased DNA damage and genomic instability, epigenetic alterations, and disrupted cell signaling, all of which cause premature senescence [10,11,12,13,14,15,16]

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