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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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Quantification of the transgenic lamin A/progerin and progerin expression in the brain and heart. (A–F) Immunofluorescent labeling of transgenic lamin A/progerin in three different regions of the brain, including the CA1 region of hippocampus, frontal cortex and the Purkinje cell layer of the cerebellum, of the HGPS animals. For both age groups, almost all cells were positive for the transgenic lamin A/progerin in the hippocampus, while in the cerebellum, there were very few positive cells. (G) Quantification of transgene-positive cells in the CA1 region of the hippocampus and the frontal cortex. (H–M) Immunofluorescent labeling of progerin in three different regions of the brain of HGPS animals. (N) Quantification of progerin-positive cells in the CA1 region of the hippocampus and the frontal cortex. (O–R) Immunofluorescent labeling of transgenic lamin A/progerin in the heart from HGPS animals at 20 or 74 weeks of age. (S and T) Quantification of cells expressing transgenic lamin A/progerin or progerin. (U–X) Immunofluorescent labeling of progerin in the ventricles and atria from the HGPS animals. Images of immunofluorescent staining were merged with DAPI. Values represent mean ± SEM (*P < 0.05, **P < 0.01–0.001, ***P < 0.001).
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DDU541F3: Quantification of the transgenic lamin A/progerin and progerin expression in the brain and heart. (A–F) Immunofluorescent labeling of transgenic lamin A/progerin in three different regions of the brain, including the CA1 region of hippocampus, frontal cortex and the Purkinje cell layer of the cerebellum, of the HGPS animals. For both age groups, almost all cells were positive for the transgenic lamin A/progerin in the hippocampus, while in the cerebellum, there were very few positive cells. (G) Quantification of transgene-positive cells in the CA1 region of the hippocampus and the frontal cortex. (H–M) Immunofluorescent labeling of progerin in three different regions of the brain of HGPS animals. (N) Quantification of progerin-positive cells in the CA1 region of the hippocampus and the frontal cortex. (O–R) Immunofluorescent labeling of transgenic lamin A/progerin in the heart from HGPS animals at 20 or 74 weeks of age. (S and T) Quantification of cells expressing transgenic lamin A/progerin or progerin. (U–X) Immunofluorescent labeling of progerin in the ventricles and atria from the HGPS animals. Images of immunofluorescent staining were merged with DAPI. Values represent mean ± SEM (*P < 0.05, **P < 0.01–0.001, ***P < 0.001).

Mentions: One feature identified in HGPS that is believed to contribute to disease progression is the accumulation of progerin during disease progression (5,10). To investigate whether transgenic lamin A and progerin proteins accumulate in different types of tissue, immunofluorescence was performed on the brain and heart using a transgenic lamin A/progerin or progerin antibody, and the number of positive cells was quantified (Fig. 3). The number of cells expressing transgenic lamin A/progerin and progerin was counted in the frontal cortex and the CA1 region of the hippocampus in 20- and 90-week-old HGPS animals. Because very few cells expressed the transgene in the cerebellum (Fig. 3C, F, J and M), the quantification was performed only on the CA1 region of the hippocampus and the frontal cortex. The labeling profile of both transgenic lamin A/progerin- and progerin-positive cells consisted of a nuclear rim (red) filled with DAPI nuclear staining (blue) (Fig. 3). The number of neurons expressing the transgenic lamin A/progerin in the CA1 region of the hippocampus was significantly higher than in the frontal cortex (P < 0.0001), but there was no difference between age groups (Fig. 3G). There was a significant increase in progerin-expressing cells in 90-week animals, both in the CA1 region of the hippocampus (P = 6.02 × 10−5) and in the frontal cortex (P = 0.004), compared with 20-week-old animals (Fig. 3N). This increase in expression was also visibly evident in the immunofluorescence images (Fig. 3H–M), especially in the CA1 region of the hippocampus (Fig. 3H and K). Furthermore, consistent with the quantification of transgenic lamin A/progerin expression, the number of cells expressing progerin in the CA1 region of the hippocampus was significantly higher than that of frontal cortex (P < 0.0001; Fig. 3N).Figure 3.


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)

Quantification of the transgenic lamin A/progerin and progerin expression in the brain and heart. (A–F) Immunofluorescent labeling of transgenic lamin A/progerin in three different regions of the brain, including the CA1 region of hippocampus, frontal cortex and the Purkinje cell layer of the cerebellum, of the HGPS animals. For both age groups, almost all cells were positive for the transgenic lamin A/progerin in the hippocampus, while in the cerebellum, there were very few positive cells. (G) Quantification of transgene-positive cells in the CA1 region of the hippocampus and the frontal cortex. (H–M) Immunofluorescent labeling of progerin in three different regions of the brain of HGPS animals. (N) Quantification of progerin-positive cells in the CA1 region of the hippocampus and the frontal cortex. (O–R) Immunofluorescent labeling of transgenic lamin A/progerin in the heart from HGPS animals at 20 or 74 weeks of age. (S and T) Quantification of cells expressing transgenic lamin A/progerin or progerin. (U–X) Immunofluorescent labeling of progerin in the ventricles and atria from the HGPS animals. Images of immunofluorescent staining were merged with DAPI. Values represent mean ± SEM (*P < 0.05, **P < 0.01–0.001, ***P < 0.001).
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DDU541F3: Quantification of the transgenic lamin A/progerin and progerin expression in the brain and heart. (A–F) Immunofluorescent labeling of transgenic lamin A/progerin in three different regions of the brain, including the CA1 region of hippocampus, frontal cortex and the Purkinje cell layer of the cerebellum, of the HGPS animals. For both age groups, almost all cells were positive for the transgenic lamin A/progerin in the hippocampus, while in the cerebellum, there were very few positive cells. (G) Quantification of transgene-positive cells in the CA1 region of the hippocampus and the frontal cortex. (H–M) Immunofluorescent labeling of progerin in three different regions of the brain of HGPS animals. (N) Quantification of progerin-positive cells in the CA1 region of the hippocampus and the frontal cortex. (O–R) Immunofluorescent labeling of transgenic lamin A/progerin in the heart from HGPS animals at 20 or 74 weeks of age. (S and T) Quantification of cells expressing transgenic lamin A/progerin or progerin. (U–X) Immunofluorescent labeling of progerin in the ventricles and atria from the HGPS animals. Images of immunofluorescent staining were merged with DAPI. Values represent mean ± SEM (*P < 0.05, **P < 0.01–0.001, ***P < 0.001).
Mentions: One feature identified in HGPS that is believed to contribute to disease progression is the accumulation of progerin during disease progression (5,10). To investigate whether transgenic lamin A and progerin proteins accumulate in different types of tissue, immunofluorescence was performed on the brain and heart using a transgenic lamin A/progerin or progerin antibody, and the number of positive cells was quantified (Fig. 3). The number of cells expressing transgenic lamin A/progerin and progerin was counted in the frontal cortex and the CA1 region of the hippocampus in 20- and 90-week-old HGPS animals. Because very few cells expressed the transgene in the cerebellum (Fig. 3C, F, J and M), the quantification was performed only on the CA1 region of the hippocampus and the frontal cortex. The labeling profile of both transgenic lamin A/progerin- and progerin-positive cells consisted of a nuclear rim (red) filled with DAPI nuclear staining (blue) (Fig. 3). The number of neurons expressing the transgenic lamin A/progerin in the CA1 region of the hippocampus was significantly higher than in the frontal cortex (P < 0.0001), but there was no difference between age groups (Fig. 3G). There was a significant increase in progerin-expressing cells in 90-week animals, both in the CA1 region of the hippocampus (P = 6.02 × 10−5) and in the frontal cortex (P = 0.004), compared with 20-week-old animals (Fig. 3N). This increase in expression was also visibly evident in the immunofluorescence images (Fig. 3H–M), especially in the CA1 region of the hippocampus (Fig. 3H and K). Furthermore, consistent with the quantification of transgenic lamin A/progerin expression, the number of cells expressing progerin in the CA1 region of the hippocampus was significantly higher than that of frontal cortex (P < 0.0001; Fig. 3N).Figure 3.

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