Abstract
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.
Highlights
Prelamin A is the major splicing product of the LMNA gene, which undergoes complex and rapid posttranslational modifications yielding mature lamin A [1]
The toxic molecule in progeroid and developmental laminopathies is prelamin A, which is subjected to rapid and modulated processing in healthy human cells [18], while it is accumulated to toxic levels in Hutchinson-Gilford progeria syndrome (HGPS), MADA and RD, as well as in Dunningan-type familial partial lipodystrophy [6, 8,9,10, 19]
The study here reported shows that rapamycin can counteract loss of factors involved in nuclear stability in MADA, leading to recovery of LAP2alpha and Oct1 localization, release of aberrant prelamin A-Oct-1 binding, SIRT-1-dependent rescue of the chromatin phenotype and shortening of prolonged S-phase associated with improvement of cell cycle dynamics
Summary
Prelamin A is the major splicing product of the LMNA gene, which undergoes complex and rapid posttranslational modifications yielding mature lamin A [1]. High levels of farnesylated prelamin A are toxic to cells, leading to nuclear envelope folding, chromatin damage www.impactaging.com. Accumulation of toxic amounts of prelamin A, either due to LMNA mutations, or due to mutation of the prelamin A endoprotease ZMPSTE24, which catalyzes protein maturation, is the molecular basis of Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral dysplasia with accelerated ageing and type A (MADA, OMIM #248370) or type B lipodystrophy (MADB) and Restrictive Dermopathy (RD, OMIM #275210), a severe developmental disorder [6, 7] [8, 9]. Accumulation of prelamin A at lower levels occurs in MADA [11] and it has been associated with recruitment of the adipocyte transcription factor SREBP1 in the nuclear periphery and impaired nuclear transactivation activity [12]. Analogous mechanisms of transcription factor sequestration at the nuclear rim have been reported for cFos, which associates with mature lamin A [13], Sp1, which binds prelamin A [14] and Oct-1, which is retained by lamin B1 [15]
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