title: 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 sensitivity to progeria disease among different organs. 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. In an attempt to clarify the origin of this phenomenon, we have developed an inducible transgenic mouse model with expression of the most common HGPS mutation in brain, skin, bone and heart to investigate how the mutation affects these organs. Ultrastructural analysis of neuronal nuclei after 70 weeks of expression of the LMNA c.1824C>T mutation showed severe distortion with multiple lobulations and irregular extensions. Despite severe distortions in the nuclei of hippocampal neurons of HGPS animals, there were only negligible changes in gene expression after 63 weeks of transgenic expression. 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.
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine.
authors.forename: Jean-Ha
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine.
authors.forename: Eva
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine.
authors.forename: Nikenza
authors.initials: N
authors.lastname: Viceconte
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Strandgren
authors.affiliation: Department of Neuroscience.
authors.forename: Karin
authors.initials: K
authors.lastname: Pernold
authors.affiliation: Department of Cell and Molecular Biology.
authors.forename: Thibaud J C
authors.initials: TJ
authors.lastname: Richard
authors.affiliation: Department of Neuroscience, Faculty of Health Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Fred W
authors.initials: FW
authors.lastname: Van Leeuwen
authors.affiliation: Department of Cell and Molecular Biology.
authors.forename: Nico P
authors.initials: NP
authors.lastname: Dantuma
authors.affiliation: Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Damberg
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.affiliation: Department of Neuroscience.
authors.forename: Brun
authors.initials: B
authors.lastname: Ulfhake
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mugnaini
authors.affiliation: Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Björn
authors.initials: B
authors.lastname: Rozell
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, maria.eriksson.2@ki.se.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson
mesh_terms: D000375:Aging / Q000235:genetics*; D019588:Aging, Premature / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D034921:Lamin Type B; C576142:Lmna protein, mouse; D012333:RNA, Messenger