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MEETING REPORT |
1 College of Biological Sciences, University of Minnesota, St. Paul.
2 Biology of Aging Program, National Institute on Aging, Bethesda, Maryland.
Address correspondence to Huber R. Warner, PhD, College of Biological Sciences, University of Minnesota, 123 Snyder Hall, 1475 Gortner Ave., St. Paul, MN 55108. E-mail: warne033{at}umn.edu
THE American Society for Cell Biology organized a meeting held in Ames, Iowa on July 21–24, 2005 titled "Nuclear Architecture and Disease." The meeting was sponsored by the Journal of Cell Biology, the Keith Porter Endowment Fund, and the National Institute of General Medical Sciences, and was chaired by Katherine Wilson (John Hopkins University) and Tom Misteli (National Cancer Institute, National Institutes of Health [NIH]). The purpose of this meeting was to bring together a critical group of investigators working on various aspects of nuclear architecture directly linked to disease, including cancer, with particular emphasis on the pathological consequences of mutations in nuclear envelope proteins. This meeting report will focus solely on the potential relevance of findings reported during the meeting to mechanisms underlying the process of aging.
Much of the meeting was devoted to mutations in LMNA, the gene encoding all A-type lamins, including lamin A, an abundant protein that forms filamentous structures within the nucleus and provides scaffolds for the assembly or activity of numerous other proteins (1). This area of research was first reviewed in 2002 by Burke and Stewart (2) when it was known that mutations in LMNA are responsible for at least six distinct pathologies including two muscular dystrophies, a lipodystrophy, a neuropathy, a skeletal and cardiac myopathy, and mandibuloacral dysplasia. However, very soon afterward, Hutchinson–Gilford progeria syndrome (HGPS) was attributed to a specific mutation at amino acid position 608 in LMNA (3,4), raising for the first time the question of whether defects in structural nuclear proteins may play a role in a segmental progeroid syndrome.
Until 2001 limited experimental work on HGPS had been attempted by gerontologists because the gene responsible for the syndrome had not been identified. Furthermore, access to patients and patient tissues was very limited, and there has been controversy about whether HGPS should be considered to represent premature aging. In January 2001, Leslie Gordon (a physician at Tufts University and the mother of an HGPS patient) founded the Progeria Research Foundation and met with representatives of several NIH institutes and the NIH Office of Rare Diseases to urge NIH staff to respond to congressional language supporting research on this rare and incurable syndrome. As a result of this meeting, an initiative was launched by the National Institute on Aging in collaboration with the Progeria Research Foundation and several other NIH Institutes that contributed to the eventual discovery that mutations in the LMNA gene activate a cryptic splice site in the messenger RNA for lamin A, leading to the production of a truncated lamin A protein (3,4).
At the 2005 American Society for Cell Biology meeting on Nuclear Architecture and Disease, Dr. Gordon described these collaborative efforts to support research on HGPS, and the surprisingly quick success in identifying the LMNA gene as the culprit testifies to the effectiveness of this public and private partnership. However, identification of the defective gene is only a first step, and even though this has not yet led to general acceptance of HGPS as an example of premature aging (5), with the help of NIH funding Dr. Gordon has developed a clinical and research database to facilitate research on HGPS in the future. New results reported at this meeting provided compelling evidence that nuclear architecture does support activities that delay aging.
Eriksson and colleagues (3) first reported that fibroblasts taken from HGPS patients contain misshapen nuclei. Such nuclear architectural defects caused by LMNA mutations occurring not only in position 608, but also elsewhere in this gene, could alter chromatin organization, patterns of gene expression, the ability of the cell to both replicate and repair DNA, and differentiation pathways. Many of these phenomena are likely to make the cells more prone to apoptosis, thus producing a systematic burden on the regenerative capacity of stem cell pools. This could potentially have implications for aging, even if the mutations such as the specific one found in HGPS patients do not occur during the normal aging process. Several presentations at this meeting described the properties of cells with a defective LMNA gene, and the results of experiments to determine what roles lamin A and/or nuclear structure in general could play during aging.
Robert Goldman (Northwestern University) and his colleagues have followed up on the initial observation that HGPS nuclei are occasionally blebbed, demonstrating that early passage HGPS fibroblasts are relatively normal, but that blebbing worsens with increasing passage number in culture, and that experimentally manipulating the ratio of normal lamin A to mutant lamin A can reproduce the changes seen in laminopathies in vivo. He has also shown that aberrant nuclear architecture reduces histone methylation and affects maintenance of the heterochromatic regions of the nuclei, presumably contributing to the pathology observed in vivo. These results support the idea that lamin A is part of an essential nuclear scaffold that is required for proper nuclear function.
Brian Kennedy (University of Washington) focused on the differentiation capabilities of myoblast and adipocyte precursors in in vitro differentiation models lacking lamin A. Lamin A–defective myoblasts show delayed differentiation in vitro, whereas adipocyte differentiation appears to be normal. Induction of MyoD, desmin, Rb protein, and M-cadherin are all reduced in these myoblasts, but myogenic potential can be restored by expression of MyoD. Dr. Kennedy proposed that the rate of muscle degeneration is increased in lamin A–deficient mice by two independent, but synergistic mechanisms; nuclear fragility may lead to muscle degeneration directly, whereas delayed expression of MyoD leads to a decreased ability to regenerate muscle. Together, these result in an inability to maintain adequate muscle mass and function.
Two presentations addressed the role of lamin A in normal aging. Paola Scaffidi (National Cancer Institute) has demonstrated that cells from old individuals do tend to have abnormal nuclear morphology. Although the cryptic splice site within the LMNA gene that is responsible for the HGPS phenotype is occasionally used in normal cells, its usage does not increase with age. Nevertheless, the aberrant nuclear morphology does increase with age, and it can be blocked with lamin A anti-sense RNA. She also reported that, in cells from old individuals, lamin A is mostly found near the inner nuclear membrane (‘peripheral’ lamina), whereas in young donors lamin A is distributed both at the periphery and throughout the nuclear interior. These results raise the possibility that lamin A could indeed be a contributing factor in normal aging.
With the same question in mind, Jun Liu (Cornell University) examined the morphology of the nuclear envelope in Caenorhabditis elegans cells during aging, and found that it changes rapidly and dramatically with increasing age in muscle, gut and dermal tissue, but not in neuronal tissue. This change in nuclear morphology is slowed by genetically reducing the activity of the insulin-signaling pathway, a well-established way to lengthen life span. Furthermore, reducing the overall lamin levels in these nuclei shortens the worm's life span, with evidence of accelerated muscle aging. A similar reduction in life span was observed in worms with reduced levels of two lamin-binding nuclear proteins (emerin and Ce-MAN1), indicating the importance of other proteins in maintaining nuclear envelope architecture and delaying aging.
The results presented at this meeting add lamin A and perhaps other structural nuclear proteins to the list of possible factors affecting the rate of aging, and suggest that gerontologists should take a fresh look at what might be learned about normal aging from studying pathologies associated with HGPS. The small stature of HGPS patients, and the time-dependent appearance of HGPS phenotypes (starting 1–2 years after birth), suggest that maintaining adequate cell number may be a critical tissue-specific problem in these children, due to excessive cell death, inadequate cell replacement, or both. It is worth considering the possibility that a similar failure to maintain functional cell numbers might play a significant role during normal aging.
Judith Campisi (Lawrence Berkeley National Laboratory and Buck Institute) concluded the meeting with a very elegant discussion, using the Bloom and Werner syndrome DNA helicases as examples, of the importance of intranuclear movement of proteins involved in DNA metabolism during the cell cycle and in response to DNA damage. She discussed what roles these two helicases plus telomerase play in maintaining genetic integrity, preventing cancer, facilitating DNA repair, postponing cell senescence, and preventing cell death. It does not stretch the imagination to consider that aberrant nuclear architecture may fail to support these activities, and thus compromise cell function and organismal survival.
Overall, the results reported at this meeting support the idea that nuclear architecture is a new frontier for research on aging, as well as disease, and that laminopathies may indeed have something to tell us about the development of pathology during normal aging.
F
Decision Editor: James R. Smith, PhD
Received September 5, 2005
Accepted October 12, 2005
References
This article has been cited by other articles:
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  J. Halaschek-Wiener and A. Brooks-Wilson Progeria of Stem Cells: Stem Cell Exhaustion in Hutchinson-Gilford Progeria Syndrome J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2007; 62(1): 3 - 8. [Abstract] [Full Text] [PDF]
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