When Lamins Go Bad: Nuclear Structure and Disease

Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Cell (Impact Factor: 32.24). 03/2013; 152(6):1365-75. DOI: 10.1016/j.cell.2013.02.015
Source: PubMed


Mutations in nuclear lamins or other proteins of the nuclear envelope are the root cause of a group of phenotypically diverse genetic disorders known as laminopathies, which have symptoms that range from muscular dystrophy to neuropathy to premature aging syndromes. Although precise disease mechanisms remain unclear, there has been substantial progress in our understanding of not only laminopathies, but also the biological roles of nuclear structure. Nuclear envelope dysfunction is associated with altered nuclear activity, impaired structural dynamics, and aberrant cell signaling. Building on these findings, small molecules are being discovered that may become effective therapeutic agents.

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    • "The LMNA gene gives rise to four types of A-type lamins via alternative splicing, with lamin A and lamin C being the two most predominant species found in mammals and lamin AD10 and lamin C2 being the less expressed ones (Cau et al., 2014). Mutations in the LMNA gene lead to a variety of disorders in humans, collectively called laminopathies (Schreiber and Kennedy, 2013). A de novo single base substitution from C to T at position 1,824 in LMNA gene exposes a cryptic splicing site and gives rise to truncated prelamin A, termed as progerin, with a 50-amino-acid deletion at the C terminus (Eriksson et al., 2003), leading to Hutchinson-Gilford progeria syndrome (HGPS), a severe form of early-onset premature aging disorder (Liu and Zhou, 2008). "
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    ABSTRACT: The nuclear lamins are essential for various molecular events in the nucleus, such as chromatin organization, DNA replication, and provision of mechanical support. A specific point mutation in the LMNA gene creates a truncated prelamin A termed progerin, causing Hutchinson-Gilford progeria syndrome (HGPS). SIRT6 deficiency leads to defective genomic maintenance and accelerated aging similar to HGPS, suggesting a potential link between lamin A and SIRT6. Here, we report that lamin A is an endogenous activator of SIRT6 and facilitates chromatin localization of SIRT6 upon DNA damage. Lamin A promotes SIRT6-dependent DNA-PKcs (DNA-PK catalytic subunit) recruitment to chromatin, CtIP deacetylation, and PARP1 mono-ADP ribosylation in response to DNA damage. The presence of progerin jeopardizes SIRT6 activation and compromises SIRT6-mediated molecular events in response to DNA damage. These data reveal a critical role for lamin A in regulating SIRT6 activities, suggesting that defects in SIRT6 functions contribute to impaired DNA repair and accelerated aging in HGPS.
    Full-text · Article · Nov 2015 · Cell Reports
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    • "Diseases caused by mutations in genes encoding nuclear lamins are generally termed laminopathies (Worman 2012). With respect to LMNA, they comprise striated muscle diseases, such as Emery- Dreifuss muscular dystrophy (EDMD) and dilated cardiomyopathy (DCM); lipodystrophic syndromes, such as familial partial lipodystrophy (FPLD); peripheral neuropathies , such as Charcot-Marie-Tooth disease; and accelerated aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS) (Schreiber and Kennedy 2013). "
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    ABSTRACT: The intermediate filament proteins, A- and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while A-type lamins lend viscosity and stiffness to nuclei. Lamins also contribute to chromatin regulation and various signaling pathways affecting gene expression. The mechanical roles of lamins and their functions in gene regulation are often viewed as independent activities, but recent findings suggest a highly cross-linked and interdependent regulation of these different functions, particularly in mechanosignaling. In this newly emerging concept, lamins act as a "mechanostat" that senses forces from outside and responds to tension by reinforcing the cytoskeleton and the extracellular matrix. A-type lamins, emerin, and the linker of the nucleoskeleton and cytoskeleton (LINC) complex directly transmit forces from the extracellular matrix into the nucleus. These mechanical forces lead to changes in the molecular structure, modification, and assembly state of A-type lamins. This in turn activates a tension-induced "inside-out signaling" through which the nucleus feeds back to the cytoskeleton and the extracellular matrix to balance outside and inside forces. These functions regulate differentiation and may be impaired in lamin-linked diseases, leading to cellular phenotypes, particularly in mechanical load-bearing tissues. © 2015 Osmanagic-Myers et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Feb 2015 · Genes & Development
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    • "Such alterations are characteristic for senescent cells and are in line with previous reports showing dissipation of the mitochondrial membrane potential in ammonia-treated cultured astrocytes (Bai et al., 2001;Kuilman et al., 2010). Deranged nuclear lamin expression as described for ammonia-treated astrocytes in the current study (Fig. 3B) and disturbed structural integrity of the nucleus are characteristic for cellular senescence and associated diseases such as progeria syndromes (Schreiber and Kennedy, 2013). Irregularly shaped nuclei have consistently been found in long-term ammoniatreated cultured astrocytes in various animal models of HE and also in the brain of patients with HE (Cavanagh and Kyu, 1971;Norenberg, 1987). "
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    ABSTRACT: Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is due to a low-grade cerebral edema associated with oxidative/nitrosative stress. Recent reports suggest that cognitive impairment in cirrhotic patients may not resolve completely after an attack of manifest HE. As astrocyte dysfunction is central to the pathogenesis of HE and astrocytes are critically involved in synaptic plasticity, we tested for sustained impairment of astrocyte function by analyzing expression levels of senescence biomarkers in ammonia-treated cultured rat astrocytes and in postmortem brain samples from cirrhotic patients with or without HE. NH4Cl time- and dose-dependently inhibited proliferation of cultured astrocytes by up to 45% (5 mmol/L, 72 h) and strongly increased senescence-associated β-galactosidase activity. Inhibition of astrocyte proliferation by ammonia was mediated by a l-methionine sulfoximine-, oxidative stress-, and p38MAPK-dependent activation of p53 associated with enhanced transcription of cell cycle inhibitory genes GADD45α and p21. Mitochondria and the nucleus were identified as sources of oxygen radical formation after prolonged NH4Cl exposure. Concurrently, NH4Cl (5 mmol/L) treatment inhibited both epidermal growth factor- and brain-derived neurotrophic factor (BDNF)-induced proliferation as well as BDNF-mediated astrocyte morphology changes through downregulation of the respective growth factor receptors epidermal growth factor receptor and truncated tyrosine receptor kinase B. Increased mRNA expression levels of senescence-associated genes were also found in post mortem brain samples from patients with liver cirrhosis with HE, but not in those without HE. The data suggest that ammonia toxicity and HE are associated with premature astrocyte senescence, which may impair neurotransmission and contribute to persistence of cognitive disturbances after resolution of episodes of overt HE. GLIA 2014
    Full-text · Article · Jan 2015 · Glia
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