Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover
Hutchinson-Gilford Progeria syndrome (HGPS) is a severe premature ageing disorder caused by a 50 amino acid truncated (Δ50AA) and permanently farnesylated lamin A (LA) mutant called progerin. On a cellular level, progerin expression leads to heterochromatin loss, impaired nucleocytoplasmic transport...
| Main Authors: | , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2024
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| Online Access: | https://hdl.handle.net/10356/178571 |
| _version_ | 1826129818211581952 |
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| author | Foo, Mattheus Xing Rong Ong, Peh Fern Yap, Zi Xuan Maric, Martina Bong, Christopher Jue Shi Dröge, Peter Burke, Brian Dreesen, Oliver |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Foo, Mattheus Xing Rong Ong, Peh Fern Yap, Zi Xuan Maric, Martina Bong, Christopher Jue Shi Dröge, Peter Burke, Brian Dreesen, Oliver |
| author_sort | Foo, Mattheus Xing Rong |
| collection | NTU |
| description | Hutchinson-Gilford Progeria syndrome (HGPS) is a severe premature ageing disorder caused by a 50 amino acid truncated (Δ50AA) and permanently farnesylated lamin A (LA) mutant called progerin. On a cellular level, progerin expression leads to heterochromatin loss, impaired nucleocytoplasmic transport, telomeric DNA damage and a permanent growth arrest called cellular senescence. Although the genetic basis for HGPS has been elucidated 20 years ago, the question whether the Δ50AA or the permanent farnesylation causes cellular defects has not been addressed. Moreover, we currently lack mechanistic insight into how the only FDA-approved progeria drug Lonafarnib, a farnesyltransferase inhibitor (FTI), ameliorates HGPS phenotypes. By expressing a variety of LA mutants using a doxycycline-inducible system, and in conjunction with FTI, we demonstrate that the permanent farnesylation, and not the Δ50AA, is solely responsible for progerin-induced cellular defects, as well as its rapid accumulation and slow clearance. Importantly, FTI does not affect clearance of progerin post-farnesylation and we demonstrate that early, but not late FTI treatment prevents HGPS phenotypes. Collectively, our study unravels the precise contributions of progerin's permanent farnesylation to its turnover and HGPS cellular phenotypes, and how FTI treatment ameliorates these. These findings are applicable to other diseases associated with permanently farnesylated proteins, such as adult-onset autosomal dominant leukodystrophy. |
| first_indexed | 2024-10-01T07:46:45Z |
| format | Journal Article |
| id | ntu-10356/178571 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:46:45Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1785712024-07-01T15:32:03Z Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover Foo, Mattheus Xing Rong Ong, Peh Fern Yap, Zi Xuan Maric, Martina Bong, Christopher Jue Shi Dröge, Peter Burke, Brian Dreesen, Oliver School of Biological Sciences LambdaGen Pte. Ltd., Singapore Medicine, Health and Life Sciences DNA damage Farnesyltransferase inhibitor Hutchinson-Gilford Progeria syndrome (HGPS) is a severe premature ageing disorder caused by a 50 amino acid truncated (Δ50AA) and permanently farnesylated lamin A (LA) mutant called progerin. On a cellular level, progerin expression leads to heterochromatin loss, impaired nucleocytoplasmic transport, telomeric DNA damage and a permanent growth arrest called cellular senescence. Although the genetic basis for HGPS has been elucidated 20 years ago, the question whether the Δ50AA or the permanent farnesylation causes cellular defects has not been addressed. Moreover, we currently lack mechanistic insight into how the only FDA-approved progeria drug Lonafarnib, a farnesyltransferase inhibitor (FTI), ameliorates HGPS phenotypes. By expressing a variety of LA mutants using a doxycycline-inducible system, and in conjunction with FTI, we demonstrate that the permanent farnesylation, and not the Δ50AA, is solely responsible for progerin-induced cellular defects, as well as its rapid accumulation and slow clearance. Importantly, FTI does not affect clearance of progerin post-farnesylation and we demonstrate that early, but not late FTI treatment prevents HGPS phenotypes. Collectively, our study unravels the precise contributions of progerin's permanent farnesylation to its turnover and HGPS cellular phenotypes, and how FTI treatment ameliorates these. These findings are applicable to other diseases associated with permanently farnesylated proteins, such as adult-onset autosomal dominant leukodystrophy. Published version This work was supported by funds from the Agency for Science, Technology and Research (A*STAR), Singapore to O.D. 2024-06-26T06:35:01Z 2024-06-26T06:35:01Z 2024 Journal Article Foo, M. X. R., Ong, P. F., Yap, Z. X., Maric, M., Bong, C. J. S., Dröge, P., Burke, B. & Dreesen, O. (2024). Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover. Aging Cell, 23(5), e14105-. https://dx.doi.org/10.1111/acel.14105 1474-9718 https://hdl.handle.net/10356/178571 10.1111/acel.14105 38504487 2-s2.0-85188553124 5 23 e14105 en Aging Cell © 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences DNA damage Farnesyltransferase inhibitor Foo, Mattheus Xing Rong Ong, Peh Fern Yap, Zi Xuan Maric, Martina Bong, Christopher Jue Shi Dröge, Peter Burke, Brian Dreesen, Oliver Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover |
| title | Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover |
| title_full | Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover |
| title_fullStr | Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover |
| title_full_unstemmed | Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover |
| title_short | Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover |
| title_sort | genetic and pharmacological modulation of lamin a farnesylation determines its function and turnover |
| topic | Medicine, Health and Life Sciences DNA damage Farnesyltransferase inhibitor |
| url | https://hdl.handle.net/10356/178571 |
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