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Afia Osei-Ntansah Ms. Kucik Independent Research GT 19 May 2014 Progerin: An Underlying Cause of Age and Age Related Diseases? Ralph Waldo Emerson, an American essayist, once said, "All diseases run into one, old age." When one gets older, there are many noticeable changes in the body. Weaker bones prone to breaks and fractures and even the progressive loss of hair are diseases of old age. Through Hutchinson Gilford Progeria Syndrome (HGPS), a rare disease characterized by accelerated aging, parallels between young patients and the aging population is found. Young children with Progeria develop symptoms and diseases that are generally found in an aging population. Weak and frail skin, thinning hair, osteoporosis and cardiovascular disease are a few of the correlations of these two contrasting groups. Knowing that there are many factors that contribute to these diseases in the normal population, there is only one main factor for disease in children with Progeria. The cause of HGPS is a mutation of the gene, lamin A. As a result of this mutation, the accumulation of the mutated protein, progerin, occurs in particular cells. As a result of progerin, the nuclear envelopes (NE) of the affected cells are aberrantly shaped indicating defects. For the reason that progerin disrupts the nuclear envelopes in specific cells of HGPS and possibly geriatric patients, progerin can be named as a factor for aging because of its effect on telomeres, osteoblasts, and vascular muscle cells (VSMCs). Hutchinson Gilford Progeria Syndrome is a rare and fatal disease which only affects approximately 1 in 4-8 million newborns (“Progeria 101/FAQ”). HGPS was first characterized as a premature aging syndrome by Drs. Jonathan Hutchinson and Hastings Gilford in 1886 and Osei-Ntansah 2 1897 (Rothman 400). This characterization was based on symptoms observed in these patients including hair loss, joint rigidity, lack of subcutaneous fat, and progressive cardiovascular disease compared to a normal aging individual (Capell and Collins 941). Before research on Progeria really began, many aspects of Progeria were unclear to researchers and doctors; therefore, there was little hope for children with Progeria. However, in April 2003, the cause of HGPS was announced to be a mutation of the lamin A gene (“Progeria 101/FAQ”). The DNA sequence of guanine-guanine-cytosine (GGC) is changed to guanine-guanine-thymine (GGT), resulting in a point mutation. However, although the sequences are different, the amino acid sequence is still the same (Nabel 221). Nonetheless, due to this silent mutation, a cryptic splice site is activated inducing an internal deletion of 150 nucleotides, or 50 amino acids (Bergo et al 2115). This truncated protein named progerin is created due to this activated splice site, consequently replacing the normal prelamin A (Nabel 221). A-type lamins are described as guardians of the soma for the reason that they are intermediate filament proteins which provide stability to the cell (Bermeo et al 5). Alterations in the interactions between lamin A and other proteins of the nuclear envelope can be the cause for the pathogenesis of age-related diseases (“LMNA” 3). With lamin A being the guardian of the soma, some may ask, “How do mutations in these proteins, expressed in nearly all somatic cells, cause different diseases,” (Brothman 403). Courvalin and Worman attempt to answer this question with the mechanical stress and gene expression hypotheses (350). The mechanical stress hypothesis suggests that abnormalities in the nucleus, which can result from lamin mutations, lead to increased susceptibility of cellular damage by physical stress (Courvalin and Worman 350). The gene expression hypothesis proposes that the nuclear envelope plays a role in tissue Osei-Ntansah 3 specific gene expression which can be altered by mutations in lamins- mutations like the one that cause Progeria (Courvalin and Worman 350). After discovering the cause of Progeria in the lamin A gene, basic biology was needed to help scientists understand the importance of lamin A. Lamin A is an intermediate filament protein whose role is to provide stability and strength to the cells (“LMNA” 2). As in most eukaryotic cells, the nuclear envelope encircles and protects the nucleus from the perpetual activity inside of the cell. A component of the nuclear envelope is the nuclear lamina, a meshwork of intermediate filament proteins found in the inner nuclear membrane (Dreesen and Stewart 889-890). Due to the basic biology of lamin A, suggestions of how progerin interacts with the nuclear envelope could be made. Capell and Collins propose that, “farnesylated progerin acts in a dominant-negative way in cells that express lamin A by becoming irreversibly anchored in the nuclear membrane” (941). Through this proposal based on the basic biology of the nuclear envelope and the nuclear lamina, further research with strong supportive reasoning could now begin. Following the knowledge of the role of lamin A, samples of fibroblasts from real patients and different types of genetically engineered mice have allowed researchers to visualize the various aspects of the nuclear envelope and the nuclear lamina. Generally, the fibroblasts models observed are knockouts of the cleavage site, Zmpste24, or mice models with the Lmna allele which can only produce progerin (Cao et. al 15902). However, depending on the independent variables and controls for the different studies, there can be several mouse models made (Michaelis). In fibroblasts from lamin A deficient mice, “the fibroblasts have misshaped nuclei with ultrastructural damage” (Courvalin and Worman 353), and the farnesylation of progerin induces “visible blebs at [the cell’s] margins, disrupted heterochromatin structure, clustering of Osei-Ntansah 4 nuclear pores and perturbation of a diverse array of downstream signaling and transcriptional events” (Capell and Collins 941). Regularly, in healthy cells, lamin proteins move between the nuclear lamina and the nucleoplasm, however, fibroblasts from patients demonstrate progerin becoming immobilized, leading to the thickening of the nuclear lamina (Rothman et. al 401). The thickening, blebbing, and clustering of the nuclear envelope support Capell and Collins’ proposition of the negative effect of progerin in the nuclear membrane of cells. Protected by the nuclear membrane are DNA, chromosomes, and also telomeres. While DNA is found wrapped around the histones, telomeres are the caps found at the tips of chromosomes and assist in maintaining its structure (Michaelis). Uncapped or shortened telomeres can be recognized as DNA damage in normal aging and can also be an indication of the presence of progerin (Courvalin and Worman 350). Dreesen and Stewart observe that “progeric fibroblasts [were shown to] have significantly shorter telomeres than age-matched controls” (891). Telomeres are also considered to be a main mechanism for replicative senescence and its length acts as a molecular clock (Magalhães). With each replication cycle, telomeres shorten stimulating a DNA damage response that in turn prompts permanent, premature growth arrest in cells (Dreesen and Stewart 891). Shortened telomeres and DNA damage are both factors that influence genomic stability and integrity (Musich and Zou 33), and are considered characteristics of normal human aging (Dreesen and Stewart 891). New knowledge due to the research of HGPS strongly suggest the general negative impact of progerin in cells. Now specifically, there is strong evidence concerning the presence of progerin in osteoclasts and osteoblasts. There are only a few cells that express lamin A and due to studies on HGPS, researchers have been able to observe which cells do and do not. Through these studies, researchers have Osei-Ntansah 5 found that progerin is expressed in osteoclasts. First, basic biology has shown that lamin A is a gene which provides structure and stability to the cells which it is expressed in. Courvalin and Worman reiterate that lamin A is essential to the integrity and quality of the bone as well (350). The integrity and quality of the bone can be determined by the quality of bone development. However, due to the expression of progerin in the bone, the osteocytes, or bone cells, are affected, “decreasing its capability to regulate bone formation” (Vidal et al. 3). One can imagine that malfunctions in this central protein can cause serious harm to bodily functions and systems – like the skeletal system. The main cells involved in the development of bones are osteoblasts (Oshima). Osteoblasts are cells which secrete the matrix for bone formation, in simpler terms, the cells which build bones up (Vidal et al. 2). From basic biology, researchers know that mutations in the lamin A gene can cause instability in the cells where lamin A is expressed. The result of this instability in osteoblasts results in a shift of the compulsory procedure of osteoblastogenesis- the process of which osteoblasts necessary for bone formation are produced- to adipogenesis (Michaelis). Adipogenesis is the name of the process where adipocytes, fat cells, are formed. Although adipogenesis is a significant procedure of the human body (Bergo et al. 2115), there is always a time and place for everything; and the location of adipogenesis in the bone cell has shown not to be the right place. Osteoblastogenesis is the process by which osteoblasts are produced. However, due to the expression of progerin, the production of osteoblasts is changed into the formation of adipocytes. This shift in bodily processes is a cause for weak and brittle bones prone to breaks and fractures in the skeletal system. This differentiation can also be associated with mechanisms of normal aging – oxidative stress, progressive DNA damage, or defective telomere activity (Vidal et al. 6). Osei-Ntansah 6 As progerin causes malfunctions in osteoclasts, it is also strongly expressed in vascular smooth muscle cells. While research has found that progerin is expressed in the skeletal system, researchers have also found that progerin is expressed and also negatively affects vascular smooth muscle cells. Indications of progerin expression can be shown through the nuclear envelope of vascular smooth muscle cells. For example, the vascular cells are misshaped due to progerin, causing blebbing of the nuclear membrane (Olive et al. 2301). Children with Progeria generally die from complications with cardiovascular disease at the average age of 13. These complications are expected due to the knowledge that the vascular smooth muscle cells are the most affected by progerin because they express the most lamin A (Cao et al. 15902). Additionally, progerin was detected in the coronary arteries of HGPS and non-HGPS individuals with coronary artery disease (Nabel 222). As many may know, atherosclerosis is a disease of the arteries characterized by the deposition of plaques with fatty material in the inner walls; however atherosclerosis can also be induced by progerin accumulation. Gordon et al. describe the observed similarities between the HGPS vascular pathology and the normal vascular pathology and one similarity was the presence of atherosclerotic lesions. In observations of the atherosclerotic lesions of HGPS and non-HGPS patients, “HGPS intimal lesions were densely fibrotic and appeared to reflect the spectrum of atheromatous lesions present in advanced aging” (Olive et al. 2303). In knowing that progerin is present in the coronary arteries of HGPS patients and non-HGPS patients, through this parallel of these lesions, there is a possibility that progerin can be a factor in the production of atheromatous lesions in the normal aging population. Osei-Ntansah 7 The major difference between Progeria patients and the normal aging population is that although “there are cardiac and vascular commonalities…there’s a lack of classical risk factors” (Olive et al. 2304). Classical risk factors of normal individuals include smoking, high blood pressure, high cholesterol, and hypertension; however, these risk factors are not found in children with Progeria because they are not old enough to develop them. Questions concerning whether Progeria shows a pure form of aging are answered through this as well, supporting the hypothesis that Progeria does present a purer form of vascular aging. While progerin causes osteocytes and vascular muscle cells to become irregularly shaped and diseases to result from this nuclear stability a drug, the farnesyltransferase inhibitor, has helped to reverse these symptoms of aging in these children. The farnesyltransferase inhibitor (FTI) is a drug that also helps to show the impact of progerin in cells that express progerin. The FTI acts by inhibiting the attachment of the farnesyl group onto progerin, therefore “paralyzing” progerin and improving phenotypes of aging in children with Progeria (Gordon 2). The FTI mislocalizes progerin from the nuclear rim, also reducing the frequency of misshapen nuclei” (Bergo et al 2116). A misshapen nucleus is one of the strongest indications of progerin expression and for disease. Additionally, after the treatment non-farnesylated levels of progerin ranged from 2% to 12% in untreated mice, 16% to 53% in mice treated with 150 mg/kg/day of the FTI, and 45% to 85% in mice treated with 450 mg/kg/day (Cao et al. 15903). These improvements of progerin farnesylation, due to the function of the FTI, can help stabilize the cells and better the symptoms of aging. For example, weakness of the skeletal system was treated with the use of the FTI. The presence of the FTI significantly improved bone development in Lmna HG/+ mutated mice (Bergo et al. 2122). When the farnesylation of progerin decelerates, the process of Osei-Ntansah 8 osteoblastogenesis can take place without much hiatus from the action of adipogenesis in the bone cells; consequently producing the necessary cells needed for bone growth and development (Vidal et al. 2). Considering this explanation, it is coherent that “the FTI treatment significantly improved, but did not completely cure, the bone disease in Lmna HG/+ mice (Bergo et al. 2121). Additionally, the use of the FTI treatment improved bone mineralization and bone cortical thickness in Lmna HG/+ mice (Vidal et al. 5). Through this, one can see how the use of a FTI has helped to reverse osteoporosis in mice models while also suggesting the use of a treatment like this in the normal aging population as well. Most commonly children with Progeria die from complications of cardiovascular disease (“Progeria 101/ FAQ” 2). Because of this, researchers focus on finding a way to treat or completely ameliorate cardiovascular disease in these children. With the FTI treatment, progerin is distanced from the nuclei of vascular smooth muscle cells, accordingly ameliorating the cardiovascular pathology in the mice. When the FTI was tested in patients of HGPS, there were also improvements of vascular stiffness- another indication of the success of the FTI (Rothman et al. 403). As Hutchinson Gilford Progeria Syndrome is characterized as an accelerated aging disease, HGPS is better defined as a pure form of accelerated aging. Progerin has been shown to be a factor for alterations in the nuclear envelopes of osteocytes and vascular muscle cells. Due to the extremity of progerin in different cases, progerin can be named as a factor for aging in the normal individual as well. Although progerin is not well known, this rare protein and this rare disease support research to provide more insight to the normal aging process. It is possible that this knowledge could be used to improve medicines for people with osteoporosis or with cardiovascular problems- the diseases of aging which are found in HGPS patients and are Osei-Ntansah 9 improved with the use of an FTI. Furthermore, this research can be used in testing the mechanical stress and gene expression hypothesis for somatic cells. An answer to how mutations in proteins can cause different diseases could not only be answered with research concerning this mutation of lamin A, but also open more doors to research on aging. Most importantly, children with Progeria could be directly impacted by advancements in research on progerin in normal aging. For example, the FTI could be improved with medications like statins which improve cardiovascular problems in the normal aging population. With the strength of a treatment like this, the lifespan of a child with Progeria could be lengthened, providing steps even closer to finding a cure. Osei-Ntansah 10 Works Cited Bergo, Martin O. Et al. “A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation.” The Journal of Clinical Investigation. Print. 1 August 2006; 116(8);2115-2121. <http://www.jci.org/ articles/ view/28968>. Cao, Kan. Et al. “A Farnesyltransferase Inhibitor Prevents Both the Onset and Late Progression of Cardiovascular Disease in a Progeria Mouse Model. “PNAS. 105.41 (2008):1590215907.Web.14 Nov. 2013. <http://www.pnas.org/content/ 105/41/15902.full>. Capell, Brian C. Collins and Francis S. “Human Laminopathies: Nuclei Gone Genetically Awry.” Nature Review Genetics 7(2006): 940-952. Web. 10 Nov 2013. Courvalin, Jean-Claude and Worman, Howard J. “How do mutations in lamin A and C cause disease?” The Journal of Clinical Investigation. 113.3. (2004): 349-351. Print. <http://www.jci.org/articles/view/20832> Dreesen, Oliver. Stewart, Colin L. “Accelerated Aging Syndromes, are the Releveant to Normal Human Aging?” Impact Aging. 3.9 (2011): 889-895. Web. 19 Nov 2013. <http://www. impactaging.com/papers/v3/n9/full/100383.html>. Gordon, Leslie B. “Update: Farnesyltransferase Inhibitors (FTIs) as Potential Drug Therapy for Children with Progeria: Recent Research Findings and Frequently Asked Questions.” Progeria Research Foundation. August 2006. PDF. 2006 . <http://progeriaresearch.org /assets/files/pdf> “LMNA.” Genetics Home Reference: Your guide to understanding genetic conditions. August 2013. Web. 16 September 2013. Michaelis, Susan. Personal Interview. 3 Jan. 2014. Osei-Ntansah 11 pio, Phillip R and Zou, Yue. “Genomic Instability and DNA Damage Responses in Progeria Arising from Defective Maturation of Prelamin A.” AGING. 1.1. (2009): n. pag. Web. 3 Nov 2013. 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