Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria
| Autor: | Stefano Squarzoni, Michela Ortolani, Giovanna Lattanzi, N.M. Maraldi, Cristina Capanni, Sandra Marmiroli, Maria Rosaria D'Apice, Giuseppe Novelli, Vittoria Cenni, Sabino Prencipe, Emanuela Scarano, Milena Fini, Marta Columbaro |
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| Přispěvatelé: | Cenni V, Capanni C, Columbaro M, Ortolani M, D'Apice MR, Novelli G, Fini M, Marmiroli S, Scarano E, Maraldi NM, Squarzoni S, Prencipe S, Lattanzi G |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Histology PROTEIN DEGRADATION Nuclear Envelope Blotting Western LAMINOPATHIES Biophysics PRELAMIN A Biology Protein degradation prelamin A autophagy protein degradation laminopathies progeria Rapamycinprelamin A autophagy protein degradation laminopathies progeria Rapamycin PROGERIA Prenylation Histone methylation medicine Humans Protein Precursors Nuclear protein Child Rapamycin lcsh:QH301-705.5 Cells Cultured Sirolimus Original Paper Progeria integumentary system Nuclear Proteins nutritional and metabolic diseases Cell Biology Fibroblasts Lamin Type A Progerin medicine.disease Chromatin Anti-Bacterial Agents Cell biology Biochemistry lcsh:Biology (General) AUTOPHAGY prelamin A progeria autophagy RAPAMYCIN Lamin |
| Zdroj: | European Journal of Histochemistry, Vol 55, Iss 4, Pp e36-e36 (2011) European Journal of Histochemistry : EJH |
| ISSN: | 2038-8306 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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