Lamins- Links To Premature Aging
Lamins are a family of type V intermediate filament proteins that are located primarily in the inner nuclear membrane. They polymerize to create the nuclear lamina. Like all intermediate filament proteins lamins contain a highly conserved α-helical coiled rod domain flanked by variable N-terminal head and C-terminal tail domains. The tail domains of lamins contain a nuclear localization signal and also contain an immunoglobulin-like fold motif. In contrast to cytoplasmic intermediate filament proteins, lamins contain consensus sites for mitotically active protein kinases, the phosphorylation of which directs the disassembly of the nuclear lamina during mitosis.
Disease associations of Lamins and their link to aging
The first disease considered to be part of the spectrum of laminopathies was Emery-Dreifuss-Muscular Dystrophy, which occurs in X-linked recessive form (X-EDMD) and also in autosomal form (AD-EDMD). X-EDMD is linked to a mutation in the EMD gene that expresses the Emerin protein, and AD-EDMD to a mutation in the LMNA gene that encodes LaminA/C. The R453W mutation in lamin A that is associated with EDMD seems likely to disrupt the structure of the tail region of lamin, and therefore to have an impact on the interaction with emerin and other nuclear lamina proteins.
One of the key features of EDMD is that only skeletal and heart muscle are affected, a surprise given the ubiquitous expression of the mutated proteins. This may be due to the complex interaction of emerin and lamin A with unknown muscle-specific factors, or to a specific lamina composition in muscle cells, rendering them more susceptible to nuclear envelope defects.
Recent work related to the role of the R482W mutation in the development of Familial Lipodystrophy (FPLD) suggest changes to the aggregation state of Lamin A/C which may impact on protein-protein and protein-DNA interactions.
Further research is needed to comprehend the intricate relationships between these essential structural proteins. It is certain that the clinical group of laminopathies will provide more information about the lamins and related proteins.
From a structural point of view a much more significant point mutation in the LMNA gene causes the ultrarare genetic disorder Hutchinson-Gilford progeria syndrome (HGPS) (estimated prevalence 1 in 18–20 million people). HGPS is characterized by accelerated aging and premature death (average lifespan, 14.6 years). Most patients with HGPS are heterozygous for a de novo synonymous mutation in the LMNA gene (c.1824C>T; p.G608G) that activates the use of a cryptic splice donor site in exon 11. The HGPS-causing mutation creates an aberrant LMNA mRNA that lacks 150 nucleotides in exon 11and this is translated into progerin, a permanently farnesylated lamin A variant that exerts a dominant-negative effect. The main medical problem in HGPS is severe cardiovascular disease, including generalized atherosclerosis and vascular calcification and stiffness. This can lead to heart attack, stroke, or heart failure, which are the main causes of death for patients with HGPS.
It is of no surprise that a condition that has often been linked to premature aging attracts much interest, as it may provide insights into the natural process of aging. This has been underpinned by observation of progerin expression in normal cells, and suggestions that it may accumulate with age.
Although the mechanisms differ from those underlying HGPS, there have been proposals that elevated levels of prelamin A may drive aspects of normal aging pathology. A new study by Primmer et al. has renewed interest in the study of lamins, and it is likely that this research will continue to be a key area of research in the coming years.
Further research is needed to comprehend the intricate relationships between these essential structural proteins. It is certain that the laminopathy diseases will provide more information about the lamins and related proteins.