Aging and nuclear organization: lamins and progeria

Mounkes, Leslie C.; Stewart, Colin L.

doi:10.1016/j.ceb.2004.03.009

Cited by 84 publications

(75 citation statements)

References 50 publications

(54 reference statements)

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“…Mutations in A-type lamins cause a spectrum of diseases ranging from EDMD to Hutchinson-Gilford progeria and atypical Werner syndrome [40]. Several studies have already shown that most A-type lamin mutations result in nuclear abnormalities, including frequent blebbing or dherniationsT, large-scale alterations in nuclear shape, increased separation of the inner and outer nuclear membranes, clustering of nuclear pores, loss of some inner nuclear membrane proteins from one pole of the nucleus, and disruption of the underlying electron-dense heterochromatin.…”

Section: Discussionmentioning

confidence: 99%

Both lamin A and lamin C mutations cause lamina instability as well as loss of internal nuclear lamin organization

Broers

Kuijpers

Östlund

et al. 2005

Experimental Cell Research

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We have applied the fluorescence loss of intensity after photobleaching (FLIP) technique to study the molecular dynamics and organization of nuclear lamin proteins in cell lines stably transfected with green fluorescent protein (GFP)-tagged A-type lamin cDNA. Normal lamin A and C proteins show abundant decoration of the inner layer of the nuclear membrane, the nuclear lamina, and a generally diffuse localization in the nuclear interior. Bleaching studies revealed that, while the GFP-tagged lamins in the lamina were virtually immobile, the intranuclear fraction of these molecules was partially mobile. Intranuclear lamin C was significantly more mobile than intranuclear lamina A.In search of a structural cause for the variety of inherited diseases caused by A-type lamin mutations, we have studied the molecular organization of GFP-tagged lamin A and lamin C mutants R453W and R386K, found in Emery-Dreifuss muscular dystrophy (EDMD), and lamin A and lamin C mutant R482W, found in patients with Dunnigan-type familial partial lipodystrophy (FPLD). In all mutants, a prominent increase in lamin mobility was observed, indicating loss of structural stability of lamin polymers, both at the perinuclear lamina and in the intranuclear lamin organization. While the lamin rod domain mutant showed overall increased mobility, the tail domain mutants showed mainly intranuclear destabilization, possibly as a result of loss of interaction with chromatin. Decreased stability of lamin mutant polymers was confirmed by flow cytometric analyses and immunoblotting of nuclear extracts.Our findings suggest a loss of function of A-type lamin mutant proteins in the organization of intranuclear chromatin and predict the loss of gene regulatory function in laminopathies.

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Section: Discussionmentioning

confidence: 99%

Both lamin A and lamin C mutations cause lamina instability as well as loss of internal nuclear lamin organization

Broers

Kuijpers

Östlund

et al. 2005

Experimental Cell Research

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“…HGPS has been suggested to be a model system for studying normal human aging (14). It is tempting to speculate that in normal individuals, prelamin A processing might become less efficient with aging because of a decrease in Zmpste24 activity.…”

Section: Lack Of Zmpste24 Processing Of Prelamin a In Human Disease Andmentioning

confidence: 99%

“…Many diseases are associated with mutations in the LMNA gene and are collectively known as laminopathies (14,15). The most common LMNA mutation associated with HGPS is a de novo mutation that activates a cryptic splice site in exon 11, leading to an internal deletion of 50 codons that includes the Zmpste24 processing site but leaves the CaaX motif intact (2,3).…”

mentioning

confidence: 99%

Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome

Mallampalli

Huyer

Bendale

et al. 2005

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

185

154

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Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disease resulting from a mutation in the LMNA gene, which encodes nuclear lamins A and C. Lamin A is synthesized as a precursor (prelamin A) with a C-terminal CaaX motif that undergoes farnesylation, endoproteolytic cleavage, and carboxylmethylation. Prelamin A is subsequently internally cleaved by the zinc metalloprotease Ste24 (Zmpste24) protease, which removes the 15 C-terminal amino acids, including the CaaX modifications, to yield mature lamin A. HGPS results from a dominant mutant form of prelamin A (progerin) that has an internal deletion of 50 aa near the C terminus that includes the Zmpste24 cleavage site and blocks removal of the CaaX-modified C terminus. Fibroblasts from HGPS patients have aberrant nuclei with irregular shapes, which we hypothesize result from the abnormal persistence of the farnesyl and͞or carboxylmethyl CaaX modifications on progerin. If this hypothesis is correct, inhibition of CaaX modification by mutation or pharmacological treatment should alleviate the nuclear morphology defect. Consistent with our hypothesis, we find that expression in HeLa cells of GFP-progerin or an uncleavable form of prelamin A with a Zmpste24 cleavage site mutation induces the formation of abnormal nuclei similar to those in HGPS fibroblasts. Strikingly, inhibition of farnesylation pharmacologically with the farnesyl transferase inhibitor rac-R115777 or mutationally by alteration of the CaaX motif dramatically reverses the abnormal nuclear morphology. These results suggest that farnesyl transferase inhibitors represent a possible therapeutic option for individuals with HGPS and͞or other laminopathies due to Zmpste24 processing defects.aging ͉ posttranslational processing ͉ laminopathy ͉ Ste24p ͉ Zarnestra

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“…Brain neurons differ profoundly from tissues susceptible to ''accelerated aging'' in at least one major respect: brain neurons are sheltered from mechanical forces by the skull. In contrast, HGPS (and most other laminopathies) appears to strike primarily the connective tissues (e.g., bone, cartilage, tendons, joints, fat, and muscle) (12,17) (20), the mechanisms of tissue degeneration that plague normal aging, and why mechanosensitive tissues deteriorate so rapidly in HGPS and other laminopathies.…”

mentioning

confidence: 99%

“…Research on the nuclear envelope and its attached network of A-and Btype lamin filaments is blossoming. Interest in this field is being fueled by the staggering variety of tissue-specific diseases and syndromes (''laminopathies'') caused by mutations in LMNA, the gene encoding A-type lamins (12). HGPS is caused by a mutation that causes missplicing of the lamin A mRNA (13).…”

mentioning

confidence: 99%

Integrity matters: Linking nuclear architecture to lifespan

Wilson

2005

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

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Aging and nuclear organization: lamins and progeria

Cited by 84 publications

References 50 publications

Both lamin A and lamin C mutations cause lamina instability as well as loss of internal nuclear lamin organization

Both lamin A and lamin C mutations cause lamina instability as well as loss of internal nuclear lamin organization

Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome

Integrity matters: Linking nuclear architecture to lifespan

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