TY - JOUR
T1 - Rapamycin treatment of Mandibuloacral Dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics
AU - Cenni, Vittoria
AU - Capanni, Cristina
AU - Mattioli, Elisabetta
AU - Columbaro, Marta
AU - Wehnert, Manfred
AU - Ortolani, Michela
AU - Fini, Milena
AU - Novelli, Giuseppe
AU - Bertacchini, Jessika
AU - Maraldi, Nadir M.
AU - Marmiroli, Sandra
AU - D'Apice, Maria Rosaria
AU - Prencipe, Sabino
AU - Squarzoni, Stefano
AU - Lattanzi, Giovanna
PY - 2014
Y1 - 2014
N2 - Lamin A is a key component of the nuclear lamina produced through post-translational processing of its precursor known as prelamin A. LMNA mutations leading to farnesylated prelamin A accumulation are known to cause lipodystrophy, progeroid and developmental diseases, including Mandibuloacral dysplasia, a mild progeroid syndrome with partial lipodystrophy and altered bone turnover. Thus, degradation of prelamin A is expected to improve the disease phenotype. Here, we show different susceptibilities of prelamin A forms to proteolysis and further demonstrate that treatment with rapamycin efficiently and selectively triggers lysosomal degradation of farnesylated prelamin A, the most toxic processing intermediate. Importantly, rapamycin treatment of Mandibuloacral dysplasia cells, which feature very low levels of the NAD-dependent sirtuin SIRT-1 in the nuclear matrix, restores SIRT-1 localization and distribution of chromatin markers, elicits release of the transcription factor Oct-1 and determines shortening of the prolonged S-phase. These findings indicate the drug as a possible treatment for Mandibuloacral dysplasia.
AB - Lamin A is a key component of the nuclear lamina produced through post-translational processing of its precursor known as prelamin A. LMNA mutations leading to farnesylated prelamin A accumulation are known to cause lipodystrophy, progeroid and developmental diseases, including Mandibuloacral dysplasia, a mild progeroid syndrome with partial lipodystrophy and altered bone turnover. Thus, degradation of prelamin A is expected to improve the disease phenotype. Here, we show different susceptibilities of prelamin A forms to proteolysis and further demonstrate that treatment with rapamycin efficiently and selectively triggers lysosomal degradation of farnesylated prelamin A, the most toxic processing intermediate. Importantly, rapamycin treatment of Mandibuloacral dysplasia cells, which feature very low levels of the NAD-dependent sirtuin SIRT-1 in the nuclear matrix, restores SIRT-1 localization and distribution of chromatin markers, elicits release of the transcription factor Oct-1 and determines shortening of the prolonged S-phase. These findings indicate the drug as a possible treatment for Mandibuloacral dysplasia.
KW - Mandibuloacral Dysplasia (MADA)
KW - Oct-1
KW - Prelamin A
KW - Rapamycin
KW - SIRT-1
UR - http://www.scopus.com/inward/record.url?scp=84907813329&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907813329&partnerID=8YFLogxK
M3 - Article
C2 - 25324471
AN - SCOPUS:84907813329
VL - 6
SP - 755
EP - 770
JO - Aging
JF - Aging
SN - 1945-4589
IS - 9
ER -