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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. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine.

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Related in: MedlinePlus

Electron microscopic analyses of nuclei of various cell types from 70-week HGPS and wild-type animals. While the wild-type hippocampus nuclei from the CA1 region consistently had a smooth round shape (A and C), the HGPS hippocampal nuclei of the CA1 region had a very irregular shape (B and K) and presented with extensive folding, blebbing and lobulation of the nuclear envelope, which was so severe that the nuclei looked fragmented (D and L). The images from the nuclear membranes (arrowheads; E and F) of the hippocampal neurons in the wild-type (E) and HGPS (F) animals showed no apparent loss of heterochromatin (arrows). (G–J) There were no significant differences in the nuclear structure of osteoblasts or osteocytes. (M) Quantification of abnormal nuclei in the hippocampus showed that 95.5% of hippocampal neurons had abnormal nuclei, compared with 11% in wild-type animals. (N and O) Nuclei of adipocytes from HGPS animals showed moderate folding and irregularity in nuclear morphology compared with wild-type animals. (P) Quantification of the percentage of adipocytes with abnormal nuclei morphology.
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DDU541F4: Electron microscopic analyses of nuclei of various cell types from 70-week HGPS and wild-type animals. While the wild-type hippocampus nuclei from the CA1 region consistently had a smooth round shape (A and C), the HGPS hippocampal nuclei of the CA1 region had a very irregular shape (B and K) and presented with extensive folding, blebbing and lobulation of the nuclear envelope, which was so severe that the nuclei looked fragmented (D and L). The images from the nuclear membranes (arrowheads; E and F) of the hippocampal neurons in the wild-type (E) and HGPS (F) animals showed no apparent loss of heterochromatin (arrows). (G–J) There were no significant differences in the nuclear structure of osteoblasts or osteocytes. (M) Quantification of abnormal nuclei in the hippocampus showed that 95.5% of hippocampal neurons had abnormal nuclei, compared with 11% in wild-type animals. (N and O) Nuclei of adipocytes from HGPS animals showed moderate folding and irregularity in nuclear morphology compared with wild-type animals. (P) Quantification of the percentage of adipocytes with abnormal nuclei morphology.

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.


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. (2014)

Electron microscopic analyses of nuclei of various cell types from 70-week HGPS and wild-type animals. While the wild-type hippocampus nuclei from the CA1 region consistently had a smooth round shape (A and C), the HGPS hippocampal nuclei of the CA1 region had a very irregular shape (B and K) and presented with extensive folding, blebbing and lobulation of the nuclear envelope, which was so severe that the nuclei looked fragmented (D and L). The images from the nuclear membranes (arrowheads; E and F) of the hippocampal neurons in the wild-type (E) and HGPS (F) animals showed no apparent loss of heterochromatin (arrows). (G–J) There were no significant differences in the nuclear structure of osteoblasts or osteocytes. (M) Quantification of abnormal nuclei in the hippocampus showed that 95.5% of hippocampal neurons had abnormal nuclei, compared with 11% in wild-type animals. (N and O) Nuclei of adipocytes from HGPS animals showed moderate folding and irregularity in nuclear morphology compared with wild-type animals. (P) Quantification of the percentage of adipocytes with abnormal nuclei morphology.
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Related In: Results  -  Collection

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DDU541F4: Electron microscopic analyses of nuclei of various cell types from 70-week HGPS and wild-type animals. While the wild-type hippocampus nuclei from the CA1 region consistently had a smooth round shape (A and C), the HGPS hippocampal nuclei of the CA1 region had a very irregular shape (B and K) and presented with extensive folding, blebbing and lobulation of the nuclear envelope, which was so severe that the nuclei looked fragmented (D and L). The images from the nuclear membranes (arrowheads; E and F) of the hippocampal neurons in the wild-type (E) and HGPS (F) animals showed no apparent loss of heterochromatin (arrows). (G–J) There were no significant differences in the nuclear structure of osteoblasts or osteocytes. (M) Quantification of abnormal nuclei in the hippocampus showed that 95.5% of hippocampal neurons had abnormal nuclei, compared with 11% in wild-type animals. (N and O) Nuclei of adipocytes from HGPS animals showed moderate folding and irregularity in nuclear morphology compared with wild-type animals. (P) Quantification of the percentage of adipocytes with abnormal nuclei morphology.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine.

Show MeSH
Related in: MedlinePlus