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...

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Main Authors: Foo, Mattheus Xing Rong, Ong, Peh Fern, Yap, Zi Xuan, Maric, Martina, Bong, Christopher Jue Shi, Dröge, Peter, Burke, Brian, Dreesen, Oliver
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2024
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Online Access:https://hdl.handle.net/10356/178571
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.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
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
DNA damage
Farnesyltransferase inhibitor
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
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.
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
format Article
author 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
title 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_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_sort genetic and pharmacological modulation of lamin a farnesylation determines its function and turnover
publishDate 2024
url https://hdl.handle.net/10356/178571
_version_ 1814047104445710336