Abstracts Category : Other

Analysis of phenotype reversibility in Hutchinson-Gilford progeria syndrome in mice

by Charlotte Strandgren

Aging affects all people and is a complex process involving both genetic and environmentalfactors in a way that is not yet completely understood. Studies of premature aging syndromesmight be helpful to acquire further clues to understand the molecular mechanisms explaininghow aging occurs. Hutchinson-Gilford progeria syndrome (HGPS or progeria) is a geneticdisease causing segmental premature aging in children, with an approximated incidence of 1in 20 million individuals. Children affected by progeria appear normal at birth, but they begindeveloping symptoms of disease within the first years of life. Symptoms of HGPS includesevere growth retardation, scleroderma-like skin changes, bone and tooth abnormalities, andloss of hair and body fat. The children with progeria die prematurely at a median age of 14.6years, due to complications from cardiovascular disease and atherosclerosis. We demonstrated that an already developed HGPS bone disease phenotype to a large extentcould be reversed in a mouse model. We also showed that the level of reversibility wasdependent on timing, since earlier transgenic suppression resulted in a better recovery of thebone phenotype. When resveratrol was assessed as a treatment option, we could only find fewbeneficial effects of the treatment. Since the human skeleton is continuously remodeled,substantial skeletal improvements could be obtained if the progeria mutation could besuppressed in patients, giving hope for the future treatment of children with progeria. We developed a conditional mouse model expressing the most common HGPS mutation inbrain, and to a less extent also in bone, skin and heart. We showed that long-term expressionof the HGPS mutation in the brain, with subsequent accumulation of progerin, resulted insevere neuronal distortions. Despite this, aged HGPS mice did not experience anyneuropathological changes or alterations in gene expression. Hence, our results suggest thatneuronal cells are less sensitive to the functional deleterious effects of progerin expression.