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

Aging affects all people and is a complex process involving both genetic and environmental factors in a way that is not yet completely understood. Studies of premature aging syndromes might be helpful to acquire further clues to understand the molecular mechanisms explaining how aging occurs. Hutchinson-Gilford progeria syndrome (HGPS or progeria) is a genetic disease causing segmental premature aging in children, with an approximated incidence of 1 in 20 million individuals. Children affected by progeria appear normal at birth, but they begin developing symptoms of disease within the first years of life. Symptoms of HGPS include severe growth retardation, scleroderma-like skin changes, bone and tooth abnormalities, and loss of hair and body fat. The children with progeria die prematurely at a median age of 14.6 years, due to complications from cardiovascular disease and atherosclerosis.

We demonstrated that an already developed HGPS bone disease phenotype to a large extent could be reversed in a mouse model. We also showed that the level of reversibility was dependent on timing, since earlier transgenic suppression resulted in a better recovery of the bone phenotype. When resveratrol was assessed as a treatment option, we could only find few beneficial effects of the treatment. Since the human skeleton is continuously remodeled, substantial skeletal improvements could be obtained if the progeria mutation could be suppressed in patients, giving hope for the future treatment of children with progeria.

We developed a conditional mouse model expressing the most common HGPS mutation in brain, and to a less extent also in bone, skin and heart. We showed that long-term expression of the HGPS mutation in the brain, with subsequent accumulation of progerin, resulted in severe neuronal distortions. Despite this, aged HGPS mice did not experience any neuropathological changes or alterations in gene expression. Hence, our results suggest that neuronal cells are less sensitive to the functional deleterious effects of progerin expression.

List of scientific papers

I. Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects. Strandgren C, Nasser HA, McKenna T, Koskela A, Tuukkanen J, Ohlsson C, Rozell B, Eriksson M. FASEB J. 2015, 29: 3193-205.
https://doi.org/10.1096/fj.14-269217

II. Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior. Baek JH, Schmidt E, Viceconte N, Strandgren C, Pernold K, Richard TJ, Van Leeuwen FW, Dantuma NP, Damberg P, Hultenby K, Ulfhake B, Mugnaini E, Rozell B, Eriksson M. Hum Mol Genet. 2015, 24: 1305-21.
https://doi.org/10.1093/hmg/ddu541

III. Expression of the Hutchinson-Gilford Progeria mutation disturbs secondary dentin formation but promotes tertiary dentin formation. Kim TH, Choi H, Strandgren C, Eriksson M, Cho ES. [Submitted]

IV. Phenotypic analysis of bone marrow from Hutchinson-Gilford progeria mice suggests a lower mesenchymal stem cell count. Strandgren C, Xiao P, Revêchon G, Qian H, Eriksson M. [Manuscript]