A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy

Lamin A and lamin C (A-type lamins, both encoded by the LMNA gene) are major components of the mammalian nuclear lamina, a complex proteinaceous structure that acts as a scaffold for protein complexes that regulate nuclear structure and function. Abnormal accumulation of farnesylated-progerin, a mutant form of prelamin A, plays a key role in the pathogenesis of the Hutchinson-Gilford progeria syndrome (HGPS), a devastating disorder that causes the death of affected children at an average age of 13.5 years, predominantly from premature atherosclerosis and myocardial infarction or stroke. Remarkably, progerin is also present in normal cells and appears to progressively accumulate during aging of non-HGPS cells. Therefore, understanding how this mutant form of lamin A provokes HGPS may shed significant insight into physiological aging. In this review, we discuss recent advances into the pathogenic mechanisms underlying HGPS, the main murine models of the disease, and the therapeutic strategies developed in cellular and animal models with the aim of reducing the accumulation of farnesylated-progerin, as well as their use in clinical trials of HGPS.V.A.’s lab is funded by the Spanish Ministry of Science and Innovation (MICINN) and the Fondo Europeo de Desarrollo Regional (FEDER) (grant SAF2007-62110), the Instituto de Salud Carlos III (ISCIII) (RECAVA, grant RD06/0014/0021), the Fundación Ramón Areces and Fina Biotech. D.P.-S. laboratory is supported by grants from the MICINN (SAF2009-11642) and ISCIII (Retics RIRAAF, RD07/0064/0007). J.M.G. is supported by the ISCIII and D.P. by the FPI programme of MICINN. The CNIC is supported by the MICINN and the Pro-CNIC Foundation.S