Hutchinson-Gilford syndrome (HGPS or progeria) is an autosomal dominant disease caused by a mutation in the LMNA gene, coding for type A lamins, which results in a truncated form of pre-lamin A called progerin. Although asymptomatic at birth, patients develop symptoms such as accelerated ageing, growth retardation and loss of vascular smooth muscle cells (VSMC) during the first year of life.
In this article, researchers from Antoine Muchir’s team* at the Institut de Myologie, in collaboration with Xavier Nissan’s (I-Stem) and Nicolas Lévy’s (Marseille) teams, investigated the mechanisms by which progerin expression leads to massive VSMC loss.
Using aorta tissue, primary cultures of mouse VSMCs from a mouse model of HGPS, and induced pluripotent stem cells (iPS) from patients, the authors :
- demonstrated the link between progerin accumulation, increased poly(ADP-Ribosyl)ation and decreased nicotinamide adenine dinucleotide (NAD+) levels in VSMCs,
- identified a new compound, trifluridine, capable of increasing NAD+ levels by decreasing the activity of poly-ADP-ribose polymerase (PARP-1), which catalyzes the poly(ADP-Ribosyl)ation of proteins with NAD+,
- showed that trifluridine treatment in vivo was able to attenuate the loss of aortic VSMCs and the clinical signs of progeria.
These results suggest a new therapeutic approach to cardiovascular disease in progeria patients.
*Signaling pathways and & striated muscles team at the Center of Research in Myology
