Molecular functions of the nuclear lamina in premature cell ageing
Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature ageing syndrome that manifests as early as 1 year of age. Patients exhibit severe phenotypes such as bone defects, cardiovascular complications, and a mean lifespan of 14 years. HGPS is caused by a silent heterozygous mutation that results i...
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| Format: | Thesis-Doctor of Philosophy |
| Language: | English |
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Nanyang Technological University
2023
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| Online Access: | https://hdl.handle.net/10356/169879 |
| _version_ | 1826123903701876736 |
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| author | Foo, Mattheus Xing Rong |
| author2 | Peter Droge |
| author_facet | Peter Droge Foo, Mattheus Xing Rong |
| author_sort | Foo, Mattheus Xing Rong |
| collection | NTU |
| description | Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature ageing syndrome that manifests as early as 1 year of age. Patients exhibit severe phenotypes such as bone defects, cardiovascular complications, and a mean lifespan of 14 years. HGPS is caused by a silent heterozygous mutation that results in a mutant form of lamin A (LA), called progerin (PG). PG expression leads to severe cellular defects such as heterochromatin loss, impaired nucleocytoplasmic transport, telomeric DNA damage and a permanent growth arrest called cellular senescence. Although PG-induced phenotypes have been well characterised, the direct mechanism of PG and how its features contribute to HGPS remain unclear. Through a combination of genetic and pharmacological approaches, we identified and characterized 3 domains of PG that contribute to the disease etiology, 2 of which are novel. Further investigation demonstrated that these domains not only affect PG-induced phenotypes, but also PG protein levels. Collectively, our research provides unprecedented molecular insight into how different domains of PG contribute to premature cell ageing. Moreover, our results lay the foundation to systematically analyse how the over 400 different LMNA mutations result in cellular dysfunction and disease. |
| first_indexed | 2024-10-01T06:11:57Z |
| format | Thesis-Doctor of Philosophy |
| id | ntu-10356/169879 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:11:57Z |
| publishDate | 2023 |
| publisher | Nanyang Technological University |
| record_format | dspace |
| spelling | ntu-10356/1698792023-09-04T07:32:08Z Molecular functions of the nuclear lamina in premature cell ageing Foo, Mattheus Xing Rong Peter Droge School of Biological Sciences A*STAR Skin Research Labs Oliver Dreesen PDroge@ntu.edu.sg; oliver_dreesen@asrl.a-star.edu.sg Science::Biological sciences Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature ageing syndrome that manifests as early as 1 year of age. Patients exhibit severe phenotypes such as bone defects, cardiovascular complications, and a mean lifespan of 14 years. HGPS is caused by a silent heterozygous mutation that results in a mutant form of lamin A (LA), called progerin (PG). PG expression leads to severe cellular defects such as heterochromatin loss, impaired nucleocytoplasmic transport, telomeric DNA damage and a permanent growth arrest called cellular senescence. Although PG-induced phenotypes have been well characterised, the direct mechanism of PG and how its features contribute to HGPS remain unclear. Through a combination of genetic and pharmacological approaches, we identified and characterized 3 domains of PG that contribute to the disease etiology, 2 of which are novel. Further investigation demonstrated that these domains not only affect PG-induced phenotypes, but also PG protein levels. Collectively, our research provides unprecedented molecular insight into how different domains of PG contribute to premature cell ageing. Moreover, our results lay the foundation to systematically analyse how the over 400 different LMNA mutations result in cellular dysfunction and disease. Doctor of Philosophy 2023-08-11T00:42:13Z 2023-08-11T00:42:13Z 2023 Thesis-Doctor of Philosophy Foo, M. X. R. (2023). Molecular functions of the nuclear lamina in premature cell ageing. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/169879 https://hdl.handle.net/10356/169879 10.32657/10356/169879 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University |
| spellingShingle | Science::Biological sciences Foo, Mattheus Xing Rong Molecular functions of the nuclear lamina in premature cell ageing |
| title | Molecular functions of the nuclear lamina in premature cell ageing |
| title_full | Molecular functions of the nuclear lamina in premature cell ageing |
| title_fullStr | Molecular functions of the nuclear lamina in premature cell ageing |
| title_full_unstemmed | Molecular functions of the nuclear lamina in premature cell ageing |
| title_short | Molecular functions of the nuclear lamina in premature cell ageing |
| title_sort | molecular functions of the nuclear lamina in premature cell ageing |
| topic | Science::Biological sciences |
| url | https://hdl.handle.net/10356/169879 |
| work_keys_str_mv | AT foomattheusxingrong molecularfunctionsofthenuclearlaminainprematurecellageing |