THE NUCLEAR ENVELOPE, SIGNALLING AND THE NUCLEAR MEMBRANE – LAMINS AND AGEING- GOOD NEWS EMERGING?
Studies have implicated Lamins in human disease for years. First in cancer, then in muscular dystrophy and cardiomyopathy, then ten years ago, in 2003 in premature ageing. Most recently, last year, Lamins have been implicated in normal ageing and Nuclear Antibodies against Lamins are now considered as universal markers of the ageing process.
Lamins ( designated A,B and C ) are so called because they make up the substantive cell structure of the nuclear lamina, the animal cell’s nucleus’ internal scaffolding. In the last few years research into the structure and function of Lamin’s has markedly increased. The reason? Ageing.
The rise in the importance of Lamins in ageing was most probably first triggered by the discovery in 2003 of the potential connection with the distressing disease of premature ageing, Progeria. Whilst it had been known prior to this that Lamin defects were linked to muscular dystrophies, lipodystrophies, cardiomyopathies and neuro pathies, the earlier emphasis appeared to focus on the structural properties of the nuclear envelope and the cell scaffolding provided by Lamins. Only later on as the research progressed was it suggested that Lamins and the nuclear lamina are far more important to cellular processes than the earlier emphasis on mere support structures might have predicted.
The culprit suggested in this new cellular process role? The gene LMNA which encodes for Lamin A and C and is implicated in more human disease pathways than any other single gene.
The Progeria connection emerged in 2003 when it was discovered that Progeria could result from an aberrantly spliced LMNA. A wide range of defects in this distressing disease e.g. a young person who ages eight time faster than a normal person, indicated the Lamins were very important to much wider range of cellular processes determined by the structures defined the cells nuclear envelope and nuclear membrane.
Researchers began to focus in earnest on the nuclear lamina and the interplay between the now two fold focus on the Lamin role- that of the support structure and as the regulator of many cellular processes. Some research focused on the well understood role the structural aspect of the nuclear lamina properties. Turns out the nuclear lamina is very elastic although not very compressible.
In Progeria, the lamina in cells cannot rearrange themselves correctly following pressure; therefore, with continued pressure it becomes compressible, making the nucleus itself brittle.
Other research focused in on changes in Lamin A that might trigger abnormalities .Lamin A undergoes a series of modifications to generate the mature proteins. A farnesyl group, a lipid-based hydrocarbon tail, gets added to Lamin A’s precursor. However the farnesyl and several amino acids are sheared off by a zinc metalloprotease.
In Progeria, however, this shearing effect doesn’t take place as it doesn’t occur because in its mutated form Lamin A lacks the relevant shearing or cleavage point. Perhaps it is the farnesyl group, that causes Progeria? Indeed this turned out to be the case – farnesyl-transferase inhibitors (FTIs), a class of drugs that inhibit farnesyl attachment, can stop the progression of or even mitigate, Progeria. It was also found that the FTIs could also improve bone density and delay disease onset in a mouse model of Progeria.
Researchers have now set their sights on the big connection- that of one between Lamins and normal ageing. Preliminary findings suggest that Lamin defects occur during ageing. Is this a response or a cause though?
Wherever the evidence leads, there does appear to be good news emerging in ageing research.