Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior
Abstract:Hutchinson–Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells, the HGPS mutation results in organ-specific defects. For example, bone and skin are strongly affected by HGPS, while the brain appears to be unaffected. There are no definite explanations as to the variable sensitiv… Show more
“…Skin sections from 120 weeks human lamin A overexpressing mice indicated a hypodermal fat layer similar to the one observed in 90 weeks wild-type mice, indicating no significant effect from the overexpression of human lamin A (Supplementary Figure S2A). In addition, the skin sections from human lamin A overexpressing mice showed a similar frequency and distribution of transgenic human lamin A expression across the skin layers as previously observed in RPE mice 20 , making it an appropriate control (Supplementary Figure S2B). Taken together, our data suggest that the adipose depot was not significantly affected by human lamin A overexpression and that progerin contributed to the observed phenotype in the RPE mice.Figure 2Progerin-expressing sWAT contributes to tissue loss.…”
Section: Resultssupporting
confidence: 64%
“…The transgenic expression was driven by the enolase promotor and was mainly expressed in the hippocampus, and to a lesser extent in skin, bone and heart 20 . In the current study, we have used the same strains of mice that we herein refer to as rare progerin expressing mice (RPE mice).…”
Accumulation of progerin is believed to underlie the pathophysiology of Hutchinson-Gilford progeria syndrome, a disease characterized by clinical features suggestive of premature aging, including loss of subcutaneous white adipose tissue (sWAT). Although progerin has been found in cells and tissues from apparently healthy individuals, its significance has been debated given its low expression levels and rare occurrence. Here we demonstrate that sustained progerin expression in a small fraction of preadipocytes and adipocytes of mouse sWAT (between 4.4% and 6.7% of the sWAT cells) results in significant tissue pathology over time, including fibrosis and lipoatrophy. Analysis of sWAT from mice of various ages showed senescence, persistent DNA damage and cell death that preceded macrophage infiltration, and systemic inflammation. Our findings suggest that continuous progerin expression in a small cell fraction of a tissue contributes to aging-associated diseases, the adipose tissue being particularly sensitive.
“…Skin sections from 120 weeks human lamin A overexpressing mice indicated a hypodermal fat layer similar to the one observed in 90 weeks wild-type mice, indicating no significant effect from the overexpression of human lamin A (Supplementary Figure S2A). In addition, the skin sections from human lamin A overexpressing mice showed a similar frequency and distribution of transgenic human lamin A expression across the skin layers as previously observed in RPE mice 20 , making it an appropriate control (Supplementary Figure S2B). Taken together, our data suggest that the adipose depot was not significantly affected by human lamin A overexpression and that progerin contributed to the observed phenotype in the RPE mice.Figure 2Progerin-expressing sWAT contributes to tissue loss.…”
Section: Resultssupporting
confidence: 64%
“…The transgenic expression was driven by the enolase promotor and was mainly expressed in the hippocampus, and to a lesser extent in skin, bone and heart 20 . In the current study, we have used the same strains of mice that we herein refer to as rare progerin expressing mice (RPE mice).…”
Accumulation of progerin is believed to underlie the pathophysiology of Hutchinson-Gilford progeria syndrome, a disease characterized by clinical features suggestive of premature aging, including loss of subcutaneous white adipose tissue (sWAT). Although progerin has been found in cells and tissues from apparently healthy individuals, its significance has been debated given its low expression levels and rare occurrence. Here we demonstrate that sustained progerin expression in a small fraction of preadipocytes and adipocytes of mouse sWAT (between 4.4% and 6.7% of the sWAT cells) results in significant tissue pathology over time, including fibrosis and lipoatrophy. Analysis of sWAT from mice of various ages showed senescence, persistent DNA damage and cell death that preceded macrophage infiltration, and systemic inflammation. Our findings suggest that continuous progerin expression in a small cell fraction of a tissue contributes to aging-associated diseases, the adipose tissue being particularly sensitive.
“…The brain, a tissue that is spared in HGPS, exhibits low levels of lamin A relative to lamin B1 (37, 45). When we ranked lamin A expression relative to lamin B1 expression, the brain was the lowest and the aorta was the highest (Fig.…”
Hutchinson-Gilford progeria syndrome is a progeroid disorder of children caused by de novo mutations in LMNA that lead to the synthesis of an internally truncated form of prelamin A (commonly called progerin). The production of progerin causes multiple disease phenotypes, including an unusual vascular phenotype characterized by the loss of smooth muscle cells in the arterial media and fibrosis of the adventitia. In this report, we show that progerin expression, combined with mechanical stress, promotes smooth muscle cell death. Disrupting the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex in smooth muscle cells ameliorates the toxic effects of progerin on smooth muscle cells and limits the accompanying adventitial fibrosis.
“…Immunohistochemical assessment of transgenic lamin A/progerin expression in femurs from 3‐week‐old untreated HGPS mice and PDO, PD3, and PD6 pups was performed as previously described (25). The frequency of transgene‐positive osteocytes was quantified in the whole diaphyseal cortical bone region as previously described (25).…”
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7 weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose alone. However, the reversal of the dental phenotype of overgrown and laterally displaced lower incisors in HGPS mice could be attributed to resveratrol. Our results indicate that the HGPS bone defects were reversible upon suppressed transgenic expression and suggest that treatments targeting aberrant progerin splicing give hope to patients who are affected by HGPS.
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