Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria
Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, lea...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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PAGEPress Publications
2011-10-01
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| Series: | European Journal of Histochemistry |
| Subjects: | |
| Online Access: | http://www.ejh.it/index.php/ejh/article/view/1895 |
| _version_ | 1818145267102253056 |
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| author | V. Cenni C. Capanni M. Columbaro M. Ortolani M.R. D'Apice G. Novelli M. Fini S. Marmiroli E. Scarano N.M. Maraldi S. Squarzoni S. Prencipe G. Lattanzi |
| author_facet | V. Cenni C. Capanni M. Columbaro M. Ortolani M.R. D'Apice G. Novelli M. Fini S. Marmiroli E. Scarano N.M. Maraldi S. Squarzoni S. Prencipe G. Lattanzi |
| author_sort | V. Cenni |
| collection | DOAJ |
| description | Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies. |
| first_indexed | 2024-12-11T12:00:44Z |
| format | Article |
| id | doaj.art-6beef72a887b45538d23a783d1c7fa8c |
| institution | Directory Open Access Journal |
| issn | 1121-760X 2038-8306 |
| language | English |
| last_indexed | 2024-12-11T12:00:44Z |
| publishDate | 2011-10-01 |
| publisher | PAGEPress Publications |
| record_format | Article |
| series | European Journal of Histochemistry |
| spelling | doaj.art-6beef72a887b45538d23a783d1c7fa8c2022-12-22T01:08:05ZengPAGEPress PublicationsEuropean Journal of Histochemistry1121-760X2038-83062011-10-01554e36e3610.4081/ejh.2011.e361227Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeriaV. Cenni0C. Capanni1M. Columbaro2M. Ortolani3M.R. D'Apice4G. Novelli5M. Fini6S. Marmiroli7E. Scarano8N.M. Maraldi9S. Squarzoni10S. Prencipe11G. Lattanzi12National Research Council of ItalyNational Research Council of ItalyRizzoli Orthopedic InstituteNational Research Council of ItalyUniversity of Tor Vergata, RomeUniversity of Tor Vergata, RomeRizzoli Orthopedic Institute and BITTA, RIT, IORUniversity of Modena and Reggio EmiliaS. Orsola-Malpighi Hospital, University of BolognaRizzoli Orthopedic InstituteNational Research Council of ItalyRizzoli Orthopedic Institute and BITTA, RIT, IORNational Research Council of ItalyFarnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.http://www.ejh.it/index.php/ejh/article/view/1895prelamin A, autophagy, protein degradation, laminopathies, progeria, Rapamycinprelamin A, autophagy, protein degradation, laminopathies, progeria, Rapamycin |
| spellingShingle | V. Cenni C. Capanni M. Columbaro M. Ortolani M.R. D'Apice G. Novelli M. Fini S. Marmiroli E. Scarano N.M. Maraldi S. Squarzoni S. Prencipe G. Lattanzi Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria European Journal of Histochemistry prelamin A, autophagy, protein degradation, laminopathies, progeria, Rapamycinprelamin A, autophagy, protein degradation, laminopathies, progeria, Rapamycin |
| title | Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria |
| title_full | Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria |
| title_fullStr | Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria |
| title_full_unstemmed | Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria |
| title_short | Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria |
| title_sort | autophagic degradation of farnesylated prelamin a as a therapeutic approach to lamin linked progeria |
| topic | prelamin A, autophagy, protein degradation, laminopathies, progeria, Rapamycinprelamin A, autophagy, protein degradation, laminopathies, progeria, Rapamycin |
| url | http://www.ejh.it/index.php/ejh/article/view/1895 |
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