Lamins A and C, in association with B-type lamins, are the major components of the nuclear lamina, located between the inner nuclear membrane and the chromatin. By interaction with a number of nuclear proteins, lamins are involved in many functions, including nuclear positioning and shape, chromatin organization, and regulation of gene transcription activity. This multi-functional aspect may account for the wide phenotype variety occurring in patients affected by mutations in the lamin A/C gene, which give rise to a growing class of genetic disorders collectively called laminopathies. These diseases (16 distinct disease phenotypes have been reported) can be grouped, on the basis of tissue and organ system involvement, as laminopathies with muscle involvements, neuronal involvements, and metabolic multiorgan involvements leading to premature senescence. Different models have been advanced to find phenotype-genotype associations that could account for the large variability in laminopathies: nuclear fragility, modifications of the nuclear envelope/chromatin relationships, alteration of gene expression, etc. Here we report evidence that, at least in the group of laminopathies with a progeric disease phenotype, LMNA mutations result in the accumulation in the nucleus of unprocessed prelamin A. This, in turn, causes an altered distribution of the lamin B receptor (LBR) and destabilization of two heterochromatin-associated proteins, HP1β and three-methylated histone H3. The resulting heterochromatin and nuclear defects can be also induced in normal cells either by using drugs that interfere with some steps of lamin A post-translational processing, or by transfection with specific LMNA mutations that lead to accumulation of unprocessed prelamin A. These results strongly suggest that the accumulation of farnesylated lamin A precursor elicits a toxic effect that results in irregular nuclear profiles with deep envelope invaginations, loss of peripheral heterochromatin, and reduction of whole transcriptional activity, mainly due to an aberrant accumulation of transcripts. This hypothesis has been confirmed by the possibility of rescuing the structural and functional alterations of progeric nuclei by a drug treatment that destabilizes the accumulated prelamin A. This has been obtained in cell lines obtained from different patients affected by the Hutchinson-Gilford progeria syndrome (HGPS), a severe pre-mature aging disorder which results in the patient death in the second decade. Our results demonstrate that the combined treatment with the farnesyl-transferase inhibitor mevinolin, and the histone deacetylase inhibitor tricostatin A, is able to greatly reduce the accumulation of mutated prelamin A, leading to rescue of the nuclear shape, heterochromatin organization and transcriptional activity in the patient's fibroblasts. These results confirm that, at least in the progeric group of laminopathies, nuclear defects are related to accumulation of unprocessed prelamin A and that they can be rectified by a pharmacological treatment.
ASJC Scopus subject areas
- Molecular Biology