Review ArticleLamin A, farnesylation and aging
Section snippets
Lamins and their processing pathway
Lamins are a family of nuclear proteins that belong to the intermediate filaments [1], [2]. Humans have two types of lamins, types A and B. A-type lamins (lamin A and C) are generated by alternative splicing of the RNA transcribed from the LMNA gene, while B-type lamins (lamins B1 and B2) are encoded by distinct transcripts originating from the LMNB1 and LMNB2 genes. There are two additional and less characterized A-type lamins: lamin C2, which was identified in human germ cells [3], [4], and
Lamin A mutations and disease
The LMNA gene is a hotspot for disease-causing mutations and has received a remarkable amount of attention because of its association with a variety of human diseases. More than four hundred mutations spanning the protein-coding region of the LMNA gene have been identified to date (http://www.umd.be/LMNA). Some of these mutations are within the region of the LMNA gene encoding for both lamin A and C, while others are unique for lamin A. These mutations cause the onset of many distinct of
Altered prelamin A metabolism disrupts cell function
The production of progerin leads to the progressive appearance of a number of cellular alterations including severe growth defects and altered nuclear membrane morphology that collectively manifest as an early onset of an aging phenotype. The affected children generally succumb to cardiovascular problems and similarities between many aspects of cardiovascular disease in progeria patient and normal adult individuals with atherosclerosis have recently been reported [20]. Ectopic expression of
Nuclear processes influenced by altered prelamin A metabolism
The molecular basis of the toxicity induced by partially processed forms of prelamin A is poorly understood but structural as well as functional deficiencies are likely to contribute to the onset of the defective phenotypes. First, lamin A is thought to provide a mechanical framework for the support of the nuclear envelope [38], [39] and accumulation of progerin or farnesylated prelamin A may cause abnormalities in the structure of the nuclear membrane and render the cell more susceptible to
Concluding remarks
Can the information gained so far be utilized for the development of therapeutic approaches to treat the diseases caused by accumulation of farnesylated mutants or intermediate forms of prelamin A? The finding that most of the effects induced by the accumulation of farnesylated prelamin A or progerin are reversible is rather gratifying, as it makes it possible to devise strategies that target the production or stability of the toxic moiety. Clinical trials that are testing the efficacy of drugs
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