p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice
Epilepsy is a complex clinical condition characterized by repeated spontaneous seizures. Seizures have been linked to multiple drivers including DNA damage accumulation. Investigation of epilepsy physiopathology in humans imposes ethical and practical limitations, for this reason model systems are m...
| Main Authors: | , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/103393 http://hdl.handle.net/10220/47298 |
| _version_ | 1824456776992423936 |
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| author | Vernì, Fiammetta Saggio, Isabella Burla, Romina La Torre, Mattia Zanetti, Giorgia Bastianelli, Alex Merigliano, Chiara Del Giudice, Simona Vercelli, Alessandro Di Cunto, Ferdinando Boido, Marina |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Vernì, Fiammetta Saggio, Isabella Burla, Romina La Torre, Mattia Zanetti, Giorgia Bastianelli, Alex Merigliano, Chiara Del Giudice, Simona Vercelli, Alessandro Di Cunto, Ferdinando Boido, Marina |
| author_sort | Vernì, Fiammetta |
| collection | NTU |
| description | Epilepsy is a complex clinical condition characterized by repeated spontaneous seizures. Seizures have been linked to multiple drivers including DNA damage accumulation. Investigation of epilepsy physiopathology in humans imposes ethical and practical limitations, for this reason model systems are mostly preferred. Among animal models, mouse mutants are particularly valuable since they allow conjoint behavioral, organismal, and genetic analyses. Along with this, since aging has been associated with higher frequency of seizures, prematurely aging mice, simulating human progeroid diseases, offer a further useful modeling element as they recapitulate aging over a short time-window. Here we report on a mouse mutant with progeroid traits that displays repeated spontaneous seizures. Mutant mice were produced by reducing the expression of the gene Ft1 (AKTIP in humans). In vitro, AKTIP/Ft1 depletion causes telomere aberrations, DNA damage, and cell senescence. AKTIP/Ft1 interacts with lamins, which control nuclear architecture and DNA function. Premature aging defects of Ft1 mutant mice include skeletal alterations and lipodystrophy. The epileptic behavior of Ft1 mutant animals was age and sex linked. Seizures were observed in 18 mutant mice (23.6% of aged ≥ 21 weeks), at an average frequency of 2.33 events/mouse. Time distribution of seizures indicated non-random enrichment of seizures over the follow-up period, with 75% of seizures happening in consecutive weeks. The analysis of epileptic brains did not reveal overt brain morphological alterations or severe neurodegeneration, however, Ft1 reduction induced expression of the inflammatory markers IL-6 and TGF-β. Importantly, Ft1 mutant mice with concomitant genetic reduction of the guardian of the genome, p53, showed no seizures or inflammatory marker activation, implicating the DNA damage response into these phenotypes. This work adds insights into the connection among DNA damage, brain function, and aging. In addition, it further underscores the importance of model organisms for studying specific phenotypes, along with permitting the analysis of genetic interactions at the organismal level. |
| first_indexed | 2025-02-19T03:59:29Z |
| format | Journal Article |
| id | ntu-10356/103393 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:59:29Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/1033932023-02-28T17:05:37Z p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice Vernì, Fiammetta Saggio, Isabella Burla, Romina La Torre, Mattia Zanetti, Giorgia Bastianelli, Alex Merigliano, Chiara Del Giudice, Simona Vercelli, Alessandro Di Cunto, Ferdinando Boido, Marina School of Biological Sciences DRNTU::Science::Biological sciences Epilepsy Aging Epilepsy is a complex clinical condition characterized by repeated spontaneous seizures. Seizures have been linked to multiple drivers including DNA damage accumulation. Investigation of epilepsy physiopathology in humans imposes ethical and practical limitations, for this reason model systems are mostly preferred. Among animal models, mouse mutants are particularly valuable since they allow conjoint behavioral, organismal, and genetic analyses. Along with this, since aging has been associated with higher frequency of seizures, prematurely aging mice, simulating human progeroid diseases, offer a further useful modeling element as they recapitulate aging over a short time-window. Here we report on a mouse mutant with progeroid traits that displays repeated spontaneous seizures. Mutant mice were produced by reducing the expression of the gene Ft1 (AKTIP in humans). In vitro, AKTIP/Ft1 depletion causes telomere aberrations, DNA damage, and cell senescence. AKTIP/Ft1 interacts with lamins, which control nuclear architecture and DNA function. Premature aging defects of Ft1 mutant mice include skeletal alterations and lipodystrophy. The epileptic behavior of Ft1 mutant animals was age and sex linked. Seizures were observed in 18 mutant mice (23.6% of aged ≥ 21 weeks), at an average frequency of 2.33 events/mouse. Time distribution of seizures indicated non-random enrichment of seizures over the follow-up period, with 75% of seizures happening in consecutive weeks. The analysis of epileptic brains did not reveal overt brain morphological alterations or severe neurodegeneration, however, Ft1 reduction induced expression of the inflammatory markers IL-6 and TGF-β. Importantly, Ft1 mutant mice with concomitant genetic reduction of the guardian of the genome, p53, showed no seizures or inflammatory marker activation, implicating the DNA damage response into these phenotypes. This work adds insights into the connection among DNA damage, brain function, and aging. In addition, it further underscores the importance of model organisms for studying specific phenotypes, along with permitting the analysis of genetic interactions at the organismal level. Published version 2019-01-02T04:48:13Z 2019-12-06T21:11:39Z 2019-01-02T04:48:13Z 2019-12-06T21:11:39Z 2018 Journal Article Burla, R., La Torre, M., Zanetti, G., Bastianelli, A., Merigliano, C., Del Giudice, S., . . . Saggio, I. (2018). p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice. Frontiers in Genetics, 9, 581-. doi:10.3389/fgene.2018.00581 https://hdl.handle.net/10356/103393 http://hdl.handle.net/10220/47298 10.3389/fgene.2018.00581 en Frontiers in Genetics © 2018 Burla, La Torre, Zanetti, Bastianelli, Merigliano, Del Giudice, Vercelli, Di Cunto, Boido, Vernì and Saggio. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. 12 p. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences Epilepsy Aging Vernì, Fiammetta Saggio, Isabella Burla, Romina La Torre, Mattia Zanetti, Giorgia Bastianelli, Alex Merigliano, Chiara Del Giudice, Simona Vercelli, Alessandro Di Cunto, Ferdinando Boido, Marina p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice |
| title | p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice |
| title_full | p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice |
| title_fullStr | p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice |
| title_full_unstemmed | p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice |
| title_short | p53-sensitive epileptic behavior and inflammation in Ft1 hypomorphic mice |
| title_sort | p53 sensitive epileptic behavior and inflammation in ft1 hypomorphic mice |
| topic | DRNTU::Science::Biological sciences Epilepsy Aging |
| url | https://hdl.handle.net/10356/103393 http://hdl.handle.net/10220/47298 |
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