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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
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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
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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
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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
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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).
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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.
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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
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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
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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.
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