Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior.
Bottom Line: In addition, low levels of progerin have also been found in several tissues from normal individuals, but it is not clear if low levels of progerin contribute to the aging of the brain.Behavioral analysis and neurogenesis assays, following long-term expression of the HGPS mutation, did not reveal significant pathology.Our results suggest that certain tissues are protected from functional deleterious effects of progerin.
Affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine.Show MeSH
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Mentions: From the immunofluorescence analyses, it was evident that the transgenic human lamin A/progerin- and progerin-positive cells in HGPS brain had abnormal nuclear morphology, with many folds and blebs (Fig. 3A–F and H–M). In order to obtain higher resolution images of neuronal nuclei, the CA1 region of the hippocampus from 70-week HGPS and wild-type animals were analyzed using transmission electron microscopy (Fig. 4). Femur and white adipose tissue from the same group of animals were also analyzed (Fig. 4). The hippocampal nuclei of HGPS animals were severely distorted, with multiple lobulations and irregular extensions, which resulted in deep invaginations of the nuclear envelope (Fig. 4B, D, K and L) compared with the normal round nuclei of the wild-type animal (Fig. 4A and C). On average, 130 hippocampal neurons were counted for each animal to quantify the number of cells with abnormal nuclei. Notably, 95.5% of hippocampal neurons of HGPS animals had either irregular shape or severe invaginations that resulted in a fragmented appearance, which was significantly higher than that of the wild-type hippocampus (Fig. 4M). It has been shown that in HGPS skin fibroblasts, peripheral heterochromatin that normally lies adjacent to the nuclear envelope is lost (5,12). Therefore, it was important to search for this loss in the hippocampal neurons of the HGPS animals. However, there was no apparent loss of peripheral heterochromatin (arrows) in HGPS hippocampal neurons compared with wild-type (Fig. 4E and F).Figure 4.
Affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine.