A-type lamins and cardiovascular disease in premature aging syndromes
Introduction
A-type lamins (Lamin A and C, encoded by the LMNA gene in human chromosome 1, National Centre for Biotechnology Information Reference Sequence NG_008692.2) are key components of the nuclear envelope [1]. Mature lamin A is generated through sequential posttranslational modifications of the precursor protein prelamin A, which normally does not accumulate in cells (Figure 1a). Maturation processing of prelamin A involves the following steps: (1) farnesylation at the cysteine residue of the C-terminal cysteine-serine-isoleucine-methionine motif (CSIM), (2) cleavage of the terminal SIM residues, (3) carboxymethylation of the farnesylcysteine, and (4) endoproteolytic removal of the 15 C-terminal aminoacids – including the farnesylcysteine α-methyl ester – by the zinc metalloprotease ZMPSTE24/FACE-1 [2]. The first three modifications render the protein more hydrophobic and facilitate its interaction with the nuclear membrane, and cleavage of the farnesyl-group increases the flexibility of lamin A once integrated in the nuclear lamina [3].
A-type lamins are expressed in most differentiated mammalian cells [1]. The lamin field has traditionally focused on the roles played by these filamentous proteins in maintaining nuclear architecture. However, groundbreaking work over the last few years has demonstrated that A-type lamins and associated nuclear envelope proteins also regulate multiple cell functions, including DNA replication and repair, higher-order chromatin organization, signal transduction, and gene transcription [4, 5]. Interest in A-type lamins has acquired added relevance with the discovery that LMNA mutations, or other genetic defects leading to changes in lamin A abundance or post-translational processing, cause at least 12 human disorders termed laminopathies [6].
Most laminopathy symptoms develop during childhood or adolescence, but some laminopathies are lethal at very young age, such as those affecting individuals with ZMPSTE24 mutations causing abnormal accumulation of farnesylated prelamin A [7] and Hutchinson–Gilford progeria syndrome (HGPS) patients, who express a mutant form of prelamin A called progerin [2, 8] (Figure 1b). HGPS has an estimated prevalence of 1 in 20 million (www.progeriaresearch.org). Most HGPS patients carry in heterozygosis a de novo dominant synonymous LMNA mutation (c.1824C>T: GGC>GGT; p.G608G) which activates an aberrant 5′ splicing site in exon 11 [9, 10]. Abnormal splicing leads to the synthesis of progerin, which lacks 50 aminoacid residues encompassing the ZMPSTE24 cleavage site. Like prelamin A, progerin retains the farnesylated modification at the C-terminus and remains permanently attached to the nuclear membrane. HGPS is characterized by severe failure to thrive, alopecia, joint contractures, scleroderma-like skin, lipodystrophy, and skeletal dysplasia [8, 11, 12••, 13]. HGPS patients also develop exacerbated cardiovascular disease (CVD), including cardiac electrical defects, atherosclerosis, vascular stiffening and calcification, and die at an average age of 14.6 years, predominantly from myocardial infarction or stroke [8, 11, 12••, 13, 14••] (Figure 2). Abnormal prelamin A accumulation caused by ZMPSTE24 mutations causes progeroid syndromes that share key features with HGPS, including premature death [7].
Cell and animal models are essential for understanding the molecular mechanisms causing progeria and for the identification of therapeutic targets [15, 16, 17]. Preclinical studies have shown that the progeroid phenotype can be ameliorated by treatment with farnesyltransferase inhibitors (FTIs) [17, 18], prompting several recent single-arm clinical trials of lonafarnib to reduce progerin toxicity. This FTI improved some aspects of cardiovascular and bone disease and audiological status in patient subgroups [19], and Kaplan–Meier survival analysis suggested increased mean survival by 1.6 years in treated patients [12]. The low efficiency of FTIs in ameliorating progeria symptoms may be caused by alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition [20]. Supporting this view, the longevity of progeroid Zmpste24-null mice is substantially extended by combined treatment with statins and aminobisphosphonates to simultaneously inhibit progerin and prelamin A farnesylation and geranylgeranylation [20]. This finding has been followed up in a ‘triple-drug’ clinical trial to evaluate the efficacy of combination therapy with an FTI (lonafarnib), a statin (pravastatin), and an aminobisphosphonate (zoledronic acid) [21••]. No participants withdrew because of side effects, and comparisons with lonafarnib monotherapy revealed an additional bone mineral density benefit; however, some patients showed increased rates of carotid and femoral arterial plaques and extraskeletal calcification, and addition of pravastatin and zoledronic acid produced no added cardiovascular benefit.
Further research is clearly needed to improve HGPS therapies and to find a cure for this devastating disease. Since CVD is the main cause of death in HGPS, here we review the molecular mechanisms by which prelamin A and progerin cause cardiovascular damage. This knowledge may shed light on the molecular mechanisms driving physiological aging and associated CVD, since progerin and prelamin A are both expressed in cells and tissues of normally aging non-HGPS individuals [2, 8].
Section snippets
Vascular smooth muscle cell loss
Alterations in vascular smooth muscle cells (VSMCs) play a major role in the development of vascular disease associated with normal and premature aging. HGPS patients exhibit VSMC loss with accumulation of matrix proteoglycans in the aorta and carotid arteries [22, 23], and similar changes have been reported in arteries from progerin-expressing mice [24, 25]. Suppression of poly (ADP-ribose) polymerase 1 (PARP1) in human VSMCs differentiated from induced pluripotent stem cells of HGPS patients
Cardiac electrical defects in progeria
Myocardial infarction and stroke resulting from widespread atherosclerosis are considered the main causes of death in HGPS [8, 11, 12••, 13]. Several studies have also demonstrated cardiac electrical defects in HGPS patients and progeroid mice. Merideth et al. performed a thorough clinical evaluation of 15 HGPS patients aged between 1 and 17 years [11]. Electrocardiographic testing showed long QT intervals in five children, including the three oldest. We recently confirmed and extended these
Concluding remarks
A-type lamins regulate nuclear architecture and multiple cell functions, including DNA replication and repair, higher-order chromatin organization, signal transduction, and gene transcription. Interest in A-type lamins has increased with the discovery that abnormal accumulation of prelamin A or its mutant form progerin cause progeroid syndromes characterized by excessive CVD and premature death. Despite major progress in the last decade, future studies are warranted to continue elucidating the
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank M. J. Andrés-Manzano for help with preparation of the figures and Simon Bartlett for English editing. Work in the laboratory of V.A. is supported by the Spanish Ministerio de Economía, Industria y Competitividad (MINECO) (SAF2013-46663-R) and the Instituto de Salud Carlos III (RD12/0042/0028) with co-funding from the Fondo Europeo de Desarrollo Regional (FEDER), the Fundació Marató TV3 (122/C/2015), and the Progeria Research Foundation (Established Investigator Award 2014-52). The CNIC
References (58)
- et al.
Progeria: a paradigm for translational medicine
Cell
(2014) - et al.
Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations
Proc Natl Acad Sci U S A
(2016) - et al.
Mouse models of laminopathies
Aging Cell
(2013) - et al.
Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient
Aging Cell
(2016) - et al.
Hutchinson–Gilford progeria syndrome as a model for vascular aging
Biogerontology
(2016) - et al.
A pathway linking oxidative stress and the Ran GTPase system in progeria
Mol Biol Cell
(2014) - et al.
Hutchinson–Gilford progeria syndrome through the lens of transcription
Aging Cell
(2013) - et al.
The lamin protein family
Genome Biol
(2011) - et al.
Hutchinson–Gilford progeria syndrome, cardiovascular disease and oxidative stress
Front Biosci
(2011) - et al.
Prelamin A processing, accumulation and distribution in normal cells and laminopathy disorders
Nucleus
(2016)
Role of A-type lamins in signaling, transcription, and chromatin organization
J Cell Biol
Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation
Annu Rev Biochem
Nuclear lamins and laminopathies
J Pathol
Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity
Hum Mol Genet
Lamin a truncation in Hutchinson–Gilford progeria
Science
Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome
Nature
Phenotype and course of Hutchinson–Gilford progeria syndrome
N Engl J Med
Impact of farnesylation inhibitors on survival in Hutchinson–Gilford progeria syndrome
Circulation
Hutchinson–Gilford progeria syndrome
Handb Clin Neurol
Hutchinson–Gilford progeria syndrome: a premature aging disease caused by LMNA gene mutations
Ageing Res Rev
Molecular insights into the premature aging disease progeria
Histochem Cell Biol
Accelerated ageing: from mechanism to therapy through animal models
Transgenic Res
Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome
Proc Natl Acad Sci U S A
Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging
Nat Med
Clinical trial of the protein farnesylation inhibitors lonafarnib, pravastatin, and zoledronic acid in children with Hutchinson–Gilford progeria syndrome
Circulation
Mechanisms of cardiovascular disease in accelerated aging syndromes
Circ Res
Cardiovascular pathology in Hutchinson–Gilford progeria: correlation with the vascular pathology of aging
Arterioscler Thromb Vasc Biol
Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson–Gilford progeria syndrome
Proc Natl Acad Sci U S A
Splicing-directed therapy in a new mouse model of human accelerated aging
Sci Trans Med
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