Histochem Cell Biol (2012) 138:643–651 number, through a treatment aimed at reducing lamin A precursor farnesylation. However, the onset of an unknown mechanism, leading to accumulation of full-length prelamin A (either farnesylated or not) in high passage MADA ﬁbroblasts, makes ineffective the treatment of cells with mevinolin. The most likely explanation for these results is that the cell requires a constant rate of farnesylated to non- farnesylated prelamin A, which is unbalanced towards farnesylated prelamin A in low passage MADA ﬁbroblasts, while it is unbalanced towards non-farnesylated prelamin A in high passage cultures. Thus, knowledge of the mecha- nism, which affects prelamin A processing in MADA, is needed in order to efﬁciently re-establish the physiological condition. Moreover, other nuclear envelope markers here used to monitor the effects of LMNA mutations on nuclear organization are two trans-membrane proteins, namely SUN1 and SUN2, which are known binding partners of prelamin A (Haque et al. 2006, 2010; Crisp et al. 2006; Mattioli et al. 2011). SUN1-increased expression has been correlated with accumulation of farnesylated prelamin A in progeria cells (Haque et al. 2010). Here, we show that MADA cells, reported to accumulate prelamin A in intra- nuclear aggregates (Capanni et al. 2005, Filesi et al. 2005), display a partial recruitment of SUN1 in these aggregates, overlapping with chromatin decondensation areas. Inter- estingly, SUN2, which does not appear to be altered in HGPS, is mislocalized in MADA. Importantly, SUN2 mislocalization in honeycomb structures is partially recovered after drug treatment, suggesting that it is mostly dependent on the accumulation of farnesylated prelamin A. To be noted, differently from what observed for the tri- H3K9, defarnesylating treatment is shown to be effective on SUN2 rescue in MADA ﬁbroblasts at any passage number, thus implying an even stronger relation between loss of farnesylated precursor, in both its partial or non-processed form, and recovery of proper distribution. Importantly, similarly to SUN2, an altered distribution of the nuclear envelope protein emerin has been previously reported in MADA (Filesi et al. 2005). Thus, we suggest that prelamin A accumulation in MADA interferes with both hetero- chromatin organization and a variety of inter-molecular interactions required for proper nuclear envelope assembly. It is known that speciﬁc tissues are prevailingly targeted in MADA: adipose tissue, skin, and certain bone segments. As in other systemic laminopathies, the accumulation of abnormal amounts of prelamin A, besides causing alter- ation in the heterochromatin pattern, can speciﬁcally interfere with the availability of tissue-speciﬁc transcrip- tion factors. This has been previously demonstrated in MADA ﬁbroblasts, in which prelamin A aggregates resulted in a reduced availability of free SREBP1, thus affecting the expression of genes involved in adipogenic differentiation (Capanni et al. 2005). 649 The study here reported suggests an additional patho- genic mechanism implicating a role for the different modiﬁcation status of NE proteins; however, the pathoge- netic signiﬁcance of SUNs mislocalization in relation to the nature of prelamin A form accumulated in MADA is not obvious. It has been suggested that alterations in lamin A/C might compromise interactions between the nucleus and cytoskeleton involved in nuclear positioning (Mejat et al. 2009; Mattioli et al. 2011). In fact, LMNA mutations have been reported to affect the linkage of the nucleus to the cytoskeleton (Schneider et al. 2010; Hale et al. 2008; Luxton et al. 2011). In a recent study, by examining nuclear movement during centrosome orientation in migrating ﬁbroblasts, which requires A-type lamins, it has been determined that LMNA mutations causing muscle diseases, block actin-dependent nuclear movement, whereas most that affect adipose tissue, such as MADA, inhibit microtubule-dependent centrosome positioning (Folker et al. 2011). Besides adipose tissue, MADA patients present a mottled cutaneous pigmentation and a sclerotic skin and osteolysis. The biological mechanism causing osteolysis in some bone segments of MADA patients is not completely understood. However, some aspects of the osteolytic process have been shown to be altered in either animal or cellular models of MADA (Avnet et al. 2011; Duque et al. 2011). We have recently provided evidence that MADA osteoblast-derived factors affect osteoclast differentiation and activity, suggest- ing that the altered bone turnover in MADA is due to up-regulation of osteoblast-derived stimulatory cytokines, including TGF beta 2, that affect osteoclast activity (Avnet et al. 2011). We previously reported that accumulation of prelamin A induced by drugs interfering with its processing results into increased osteoclast differentiation from human peripheral blood monocytes (Zini et al. 2008). Here, we propose that mislocalization of SUN1 and SUN2 occurring in MADA cells contributes to dysregulation of the mech- anism of cell fusion, which is required for osteoclast for- mation. Further, a general mechanism of nuclear positioning implicated in bone, adipocyte and muscle dif- ferentiation and depending on SUN proteins and the LINC complex (Folker et al. 2011; Mattioli et al. 2011; Starr 2009) may play a role in MADA pathogenesis. The results here reported also suggest that, whichever pathogenic mechanism could be activated through farn- esylated prelamin A accumulation, mevinolin, and mostly mevinolin plus TSA (Columbaro et al. 2005), are effective in the recovery of both chromatin arrangement and of proper SUN2 organization. The effects of drug treatments reported in this study give new important insights. First, molecules involved in MADA pathogenesis are not only those regulating chro- matin organization but contingently also the integral 123