Review Article
Lamin A, farnesylation and aging

https://doi.org/10.1016/j.yexcr.2011.08.009Get rights and content

Abstract

Lamin A is a component of the nuclear envelope that is synthesized as a precursor prelamin A molecule and then processed into mature lamin A through sequential steps of posttranslational modifications and proteolytic cleavages. Remarkably, over 400 distinct point mutations have been so far identified throughout the LMNA gene, which result in the development of at least ten distinct human disorders, collectively known as laminopathies, among which is the premature aging disease Hutchinson–Gilford progeria syndrome (HGPS). The majority of HGPS cases are associated with a single point mutation in the LMNA gene that causes the production of a permanently farnesylated mutant lamin A protein termed progerin. The mechanism by which progerin leads to premature aging and the classical HGPS disease phenotype as well as the relationship between this disorder and the onset of analogous symptoms during the lifespan of a normal individual are not well understood. Yet, recent studies have provided critical insights on the cellular processes that are affected by accumulation of progerin and have suggested that cellular alterations in the lamin A processing pathway leading to the accumulation of farnesylated prelamin A intermediates may play a role in the aging process in the general population. In this review we provide a short background on lamin A and its maturation pathway and discuss the current knowledge of how progerin or alterations in the prelamin A processing pathway are thought to influence cell function and contribute to human 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

References (77)

  • L. Hernandez et al.

    Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria

    Dev. Cell

    (2010)
  • J.M. Bridger et al.

    Aging of Hutchinson–Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis

    Exp. Gerontol.

    (2004)
  • J. Zhang et al.

    A human iPSC model of Hutchinson Gilford progeria reveals vascular smooth muscle and mesenchymal stem cell defects

    Cell Stem Cell

    (2011)
  • U. Aebi et al.

    The nuclear lamina is a meshwork of intermediate-type filaments

    Nature

    (1986)
  • A.E. Goldman et al.

    Keratin-like proteins that coisolate with intermediate filaments of BHK-21 cells are nuclear lamins

    Proc. Natl. Acad. Sci. U. S. A.

    (1986)
  • Y. Liu et al.

    DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A

    J. Cell Sci.

    (2006)
  • M. Sinensky et al.

    The processing pathway of prelamin A

    J. Cell Sci.

    (1994)
  • S. Dominici et al.

    Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria

    Eur. J. Histochem.

    (2009)
  • H. Hennekes et al.

    The role of isoprenylation in membrane attachment of nuclear lamins. A single point mutation prevents proteolytic cleavage of the lamin A precursor and confers membrane binding properties

    J. Cell Sci.

    (1994)
  • R.J. Lutz et al.

    Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina

    Proc. Natl. Acad. Sci. U. S. A.

    (1992)
  • J.L. Broers et al.

    Nuclear lamins: laminopathies and their role in premature ageing

    Physiol. Rev.

    (2006)
  • J. Ackerman et al.

    Hutchinson–Gilford progeria syndrome: a pathologic study

    Pediatr. Pathol. Mol. Med.

    (2002)
  • R.L. Pollex et al.

    Hutchinson–Gilford progeria syndrome

    Clin. Genet.

    (2004)
  • M. Eriksson et al.

    Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome

    Nature

    (2003)
  • A. De Sandre-Giovannoli et al.

    Lamin a truncation in Hutchinson–Gilford progeria

    Science

    (2003)
  • R.C. Hennekam

    Hutchinson–Gilford progeria syndrome: review of the phenotype

    Am. J. Med. Genet. A

    (2006)
  • T. Dechat et al.

    Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • R. Varga et al.

    Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson–Gilford progeria syndrome

    Proc. Natl. Acad. Sci. U. S. A.

    (2006)
  • S.H. Yang et al.

    Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson–Gilford progeria syndrome mutation

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • M. Olive et al.

    Cardiovascular pathology in Hutchinson–Gilford progeria: correlation with the vascular pathology of aging

    Arterioscler. Thromb. Vasc. Biol.

    (2010)
  • A.K. Agarwal et al.

    Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia

    Hum. Mol. Genet.

    (2003)
  • C.L. Navarro et al.

    Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors

    Hum. Mol. Genet.

    (2005)
  • P. Scaffidi et al.

    Lamin A-dependent nuclear defects in human aging

    Science

    (2006)
  • D. McClintock et al.

    The mutant form of lamin A that causes Hutchinson–Gilford progeria is a biomarker of cellular aging in human skin

    PLoS ONE

    (2007)
  • C.D. Ragnauth et al.

    Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging

    Circulation

    (2010)
  • J. Candelario et al.

    Perturbation of wild-type lamin A metabolism results in a progeroid phenotype

    Aging Cell

    (2008)
  • E. Koshimizu et al.

    Embryonic senescence and laminopathies in a progeroid zebrafish model

    PLoS One

    (2011)
  • B.A. Kudlow et al.

    Suppression of proliferative defects associated with processing-defective lamin Amutants by hTERT or inactivation of p53

    Mol. Biol. Cell

    (2008)
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