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. In Paper I, 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. In Paper II, 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. In Paper III, in order to gain deeper knowledge of how the teeth are affected in HGPS, we further characterized the mandibular molars of our bone-specific mouse model expressing the most common HGPS mutation in osteoblasts, osteocytes and odontoblasts. We show that progerin expression significantly disturbs secondary dentin formation and that excessive deposition of irregular tertiary dentin takes place. Our findings could be used to elucidate the mechanisms involved in formation of reparative tertiary dentin, which might be applicable in a clinical setting to stimulate tertiary dentin formation. In Paper IV, the skeletal phenotype of a previously developed knock-in mouse model with systemic expression of progerin was characterized. Progeria mice showed a significantly higher frequency of empty osteocyte lacunae in cortical bone tissue as well as a higher incidence of ribcage calluses compared to wild-type mice. Bone marrow phenotyping showed that the mesenchymal stem cell population was impaired, and mesenchymal stem cells showed an increased adipogenic and osteogenic differentiation capacity compared to wildtype mice. Our results suggest that mesenchymal stem cell transplantation from healthy donors might be a treatment strategy for HGPS that could be tested in this mouse model. 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 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. *Equal contribution 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. Manuscript submitted. *Equal contribution 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