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

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.

Calcitriol Prevents RAD51 Loss and cGAS‐STING‐IFN Response Triggered by Progerin

“…As control of the effectiveness of calcitriol treatment, we found a marked upregulation of CYP24A1 , a gene controlled by VDR signaling. This was accompanied by a decrease in progerin transcript levels, supporting our previous findings in HGPS patient derived fibroblasts …”

“…As shown in Figure 2B, induction of GFP‐progerin results in a marked decrease in RAD51 levels, as early as 1 day after doxycycline addition, coinciding with RFI (Figure 1B). The downregulation of RAD51 is accompanied by decreased levels of vitamin D receptor (VDR), as previously reported in progerin‐expressing cells, and followed by increased levels of phosphorylated RPA on residue Ser33 (P‐RPA S33 ), a marker of RS. Furthermore, we find that expression of progerin does lead to increased levels of cGAS, STING, and ISG15, as previously reported .…”

“…Next, we monitored the levels and localization of 53BP1, a key factor in DNA repair by non‐homologous end‐joining, previously shown to be degraded during extended proliferation of HGPS cells in culture . We did not find alterations in the levels of 53BP1 ( Figure 3A) or its ability to form foci at sites of DNA damage induced by progerin (Figure 3B) in this inducible cellular system.…”

“…Our previous studies in progerin‐expressing cells revealed accumulation of DNA damage and replication stress (RS) . In fact, the replication defects in progerin‐expressing cells are more robust than in lamin‐depleted cells, causing replication fork (RF) stalling in addition to fork degradation by nucleases .…”

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

“…These findings stress the importance of testing in vivo the efficacy of retinoids in ameliorating HGPS defects without inducing toxicity. Furthermore, our recent studies show that activation of vitamin D receptor signaling by ligand (1,25α-dihydroxy-vitamin D 3 ) binding ameliorates a broad repertoire of phenotypes of HGPS patient-derived cells (Kreienkamp, Croke et al 2016). It is likely that combination therapy is the best strategy to obtain synergy among these compounds, while reducing toxicity owed to lowering the doses of each single compound.…”