Metformin decreases progerin expression and alleviates pathological defects of Hutchinson-Gilford progeria syndrome cells.

Nicolas Levy,Marc Peschanski,Anne-Laure Jaskowiak,Annachiara De Sandre-Giovannoli,Sophie Blondel,Alessandra Lo Cicero,Anne-Laure Egesipe,Xavier Nissan,Claire Navarro

doi:10.1038/npjamd.2016.26

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, LmnaG609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease.

Highlights

Lamin A and lamin C are two structural proteins in the nuclear membrane that are expressed the same LMNA gene by alternative splicing.[1]
Pharmacological inhibition of SRSF1 has already been experimentally described as a potential therapeutic approach to modulate alternative splicing of SRSF1-targeted genes through the inhibition of the protein kinase SRPK1.15–17 several compounds were described, such as SRPIN340, MVRL09 or SPHINX, none of these pharmacological agents is applicable as such for the systemic treatment required for Hutchinson–Gilford progeria syndrome (HGPS) owing to potential toxicity
Because SRSF1 was reported to regulate the balance between A-type lamins, their expression was measured 48 h after metformin treatment, showing a correlated dose-dependent decrease in lamin A and progerin expression, with a maximum effect at 5 mmol/l (Figure 1d)

Summary

Introduction

Lamin A and lamin C are two structural proteins in the nuclear membrane that are expressed the same LMNA gene by alternative splicing.[1]. In 2011, the RNA-binding protein SRSF1 (for serine/arginine-rich splicing factor 1) was shown to affect alternative splicing of LMNA in human HGPS primary fibroblasts and mouse LmnaG609G/G609G fibroblasts.[14] Pharmacological inhibition of SRSF1 has already been experimentally described as a potential therapeutic approach to modulate alternative splicing of SRSF1-targeted genes through the inhibition of the protein kinase SRPK1.15–17 several compounds were described, such as SRPIN340, MVRL09 or SPHINX, none of these pharmacological agents is applicable as such for the systemic treatment required for HGPS owing to potential toxicity This toxicity issue may be resolved by a recent whole-genome transcriptomic analysis that has revealed that SRSF1 expression is transcriptionally regulated by the antidiabetic drug metformin,[18] which has demonstrated a good safety profile in millions of patients over the past two decades

Methods

Results

Conclusion