Interesting research on Progeria and aging
From an email list archive I'm slowly catching up on:
Looks like this group is doing some very interesting work in the area of Progeria (basically these are premature aging diseases), with possible knock-on consequences for (anti-)aging in general...
Date: Tue, 2 May 2006 19:59:51 -0700 (PDT)
From: Doug Skrecky
Subject: mutated lamin A likely key driver of human
aging
[Farnesyltransferase inhibitors or lamin A specific
oligonucleotides offer the prospect of effective
treatments for Hutchinson-Gilford progeria. Since the
Lamin A defect responsible for this progeria also
plays a role in normal human aging, this raises the
interesting possibility of a significant increase in
the normal human lifespan in the near future.
Treatment of those suffering from progeria is expected
shortly.]
Science. 2006 Apr 27; [Epub ahead of print]
Lamin A-Dependent Nuclear Defects in Human Aging.
Scaffidi P, Misteli T.
National Cancer Institute, NIH, Bethesda, MD 20892
USA.
Mutations in the nuclear structural protein lamin A
cause the premature aging syndrome Hutchinson-Gilford
Progeria (HGPS). Whether lamin A plays any role in the
normal aging process is unknown. Here we show that the
same molecular mechanism responsible for HGPS is
active in healthy cells. Cell nuclei from old
individuals acquire similar defects as HGPS
patient cells including changes in histone
modifications and increased DNA damage. Age-related
nuclear defects are caused by sporadic use in
healthy individuals of the same cryptic splice site in
lamin A whose constitutive activation causes HGPS.
Inhibition of this splice site reverses the nuclear
defects associated with aging. These observations
implicate lamin A in physiological aging.
J Clin Invest. 2006 Mar;116(3):743-52.
Prelamin A and lamin A appear to be dispensable in the
nuclear lamina.
Lamin A and lamin C, both products of Lmna, are key
components of the nuclear lamina. In the mouse, a
deficiency in both lamin A and lamin C leads to slow
growth, muscle weakness, and death by 6 weeks of
age. Fibroblasts deficient in lamins A and C contain
misshapen and structurally weakened nuclei, and emerin
is mislocalized away from the nuclear envelope. The
physiologic rationale for the existence of the 2
different Lmna products lamin A and lamin C is
unclear, although several reports have suggested that
lamin A may have particularly important
functions, for example in the targeting of emerin and
lamin C to the nuclear envelope. Here we report the
development of lamin C-only mice (Lmna(LCO/LCO)),
which produce lamin C but no lamin A or prelamin A
(the precursor to lamin A). Lmna(LCO/LCO) mice were
entirely healthy, and Lmna(LCO/LCO) cells displayed
normal emerin targeting and exhibited only very
minimal alterations in nuclear shape and nuclear
deformability. Thus, at least in the mouse, prelamin A
and lamin A appear to be dispensable. Nevertheless, an
accumulation of farnesyl-prelamin A (as occurs with a
deficiency in the prelamin A processing enzyme
Zmpste24) caused dramatically misshapen nuclei and
progeria-like disease phenotypes. The apparent
dispensability of prelamin A suggested that
lamin A-related progeroid syndromes might be treated
with impunity by reducing prelamin A synthesis.
Remarkably, the presence of a single Lmna(LCO) allele
eliminated the nuclear shape abnormalities and
progeria-like disease phenotypes in Zmpste24-/- mice.
Moreover, treating Zmpste24-/- cells with a prelamin
A-specific antisense oligonucleotide reduced prelamin
A levels and significantly reduced the frequency of
misshapen nuclei. These studies suggest a new
therapeutic strategy for treating progeria and other
lamin A diseases.
Science. 2006 Mar 17;311(5767):1621-3. Epub 2006 Feb
16.
A protein farnesyltransferase inhibitor ameliorates
disease in a mouse model of progeria.
Progerias are rare genetic diseases characterized by
premature aging. Several progeroid disorders are
caused by mutations that lead to the accumulation of a
lipid-modified (farnesylated) form of prelamin A,
a protein that contributes to the structural
scaffolding for the cell nucleus. In progeria, the
accumulation of farnesyl-prelamin A disrupts
this scaffolding, leading to misshapen nuclei.
Previous studies have shown that farnesyltransferase
inhibitors (FTIs) reverse this cellular
abnormality. We tested the efficacy of an FTI
(ABT-100) in Zmpste24-deficient mice, a mouse model of
progeria. The FTI-treated mice exhibited improved body
weight, grip strength, bone integrity, and percent
survival at 20 weeks of age. These results suggest
that FTIs may have beneficial effects in humans with
progeria.
[Interesting that nuclear deformation is here
associated with proliferation defects. Some believe
this to be the major reason for escalating
age-associated mortality risks from vascular disease.]
Cell Biol Int. 2005 Dec;29(12):1032-7. Epub 2005 Nov
28.
Nuclear deformation characterizes Werner syndrome
cells.
Mutations in the lamin A gene have been shown, among
other defects, to give rise to Hutchinson-Gilford
progeria syndrome (HGPS) and to atypical Werner
syndrome (WS), both of which are progeroid disorders.
Here, we have investigated well-characterized WS
patient cell strains that are compound heterozygous
for mutations in the WRN gene. As in HGPS and in
atypical WS, we found nuclear deformations to be
characteristic of all cell strains studied. In WS
cells centrosome number, assembly of the nuclear
lamina and nuclear pore distribution occurred
normally. Furthermore, nuclear deformations were not
associated with a defect in lamin A expression. We
propose that nuclear deformation is a universal
characteristic of progeroid cells and may result from
slow cell cycle progression.
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16690-5.
Epub 2005 Nov 3.
Age-related changes of nuclear architecture in
Caenorhabditis elegans.
Mutations in lamins cause premature aging syndromes in
humans, including the Hutchinson-Gilford Progeria
Syndrome (HGPS) and Atypical Werner Syndrome. It has
been shown that HGPS cells in culture undergo
age-dependent progressive changes in nuclear
architecture. However, it is unknown whether similar
changes in nuclear architecture occur during
the normal aging process. We have observed that major
changes of nuclear architecture accompany
Caenorhabditis elegans aging. We found that the
nuclear architecture in most nonneuronal cell types
undergoes progressive and stochastic age-dependent
alterations, such as changes of nuclear shape and loss
of peripheral heterochromatin. Furthermore, we show
that the rate of these alterations is influenced by
the insulin/IGF-1 like signaling pathway and that
reducing the level of lamin and lamin-associated LEM
domain proteins leads to shortening of lifespan.
Our work not only provides evidence for changes of
nuclear architecture during the normal aging process
of a multicellular organism, but also suggests that
HGPS is likely a result of acceleration of the normal
aging process. Because the nucleus is vital for many
cellular functions, our studies raise the possibility
that the nucleus is a prominent focal point for
regulating aging.
Hum Genet. 2005 Dec;118(3-4):444-50. Epub 2005 Oct 6.
Correction of cellular phenotypes of
Hutchinson-Gilford Progeria cells by RNA interference.
The great majority of cases of the Hutchinson-Gilford
progeroid syndrome (HGPS) ("Progeria of Childhood'')
are caused by a single nucleotide mutation (1824 C->T)
in the LMNA gene which encodes lamin A and C, nuclear
intermediate filaments that are important components
of
the nuclear lamina. The resultant mutant protein
(Delta50 lamin A) is thought to act in a dominant
fashion. We exploited RNA interference technology to
suppress Delta50 lamin A expression, with the long
range goal of intervening in the pathogenesis of the
coronary artery atherosclerosis that typically leads
to the death of HGPS patients.
Short hairpin RNA (shRNA) constructs were designed to
target the mutated pre-spliced or mature LMNA mRNAs,
and were expressed in HGPS fibroblasts carrying the
1824 C->T mutations using lentiviruses. One of the
shRNAs targeted to the mutated mRNA reduced the
expression levels of Delta50 lamin A to 26% or lower.
The reduced expression was associated with
amelioration of abnormal nuclear morphology,
improvement of proliferative potential, and reduction
in the numbers of senescent cells. These findings
provide a rationale for potential gene therapy.
J Lipid Res. 2005 Dec;46(12):2531-58. Epub 2005 Oct 5.
Prelamin A, Zmpste24, misshapen cell nuclei, and
progeria--new evidence suggesting that protein
farnesylation could be important for disease
pathogenesis.
Prelamin A undergoes multistep processing to yield
lamin A, a structural protein of the nuclear lamina.
Prelamin A terminates with a CAAX motif, which
triggers farnesylation of a C-terminal cysteine (the
C of the CAAX motif), endoproteolytic release of the
last three amino acids (the AAX), and methylation of
the newly exposed farnesylcysteine residue. In
addition, prelamin A is cleaved a second time,
releasing 15 more residues from the C terminus
(including the farnesylcysteine methyl ester),
generating mature lamin A. This second cleavage step
is carried out by an endoplasmic reticulum membrane
protease, ZMPSTE24. Interest in the posttranslational
processing of prelamin A has increased with the
recognition that certain progeroid syndromes can be
caused by mutations that lead to an accumulation of
farnesyl-prelamin A. Recently, we showed that a key
cellular phenotype of these progeroid disorders,
misshapen cell nuclei, can be ameliorated by
inhibitors of protein farnesylation, suggesting a
potential strategy for treating these diseases. In
this
article, we review the posttranslational processing of
prelamin A, describe several mouse models for
progeroid syndromes, explain the mutations underlying
several human progeroid syndromes, and summarize
recent data showing that misshapen nuclei can be
ameliorated by treating cells with protein
farnesyltransferase inhibitors.
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14416-21.
Epub 2005 Sep 26.
Inhibiting farnesylation reverses the nuclear
morphology defect in a HeLa cell model for
Hutchinson-Gilford progeria syndrome.
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 and/or 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 and/or
other laminopathies due to Zmpste24 processing
defects.
[Blocking the manufacture of mutated lamin A with a
modified oligonucleotide reverses progeria in the test
tube as well.]
Nat Med. 2005 Apr;11(4):440-5. Epub 2005 Mar 6.
Reversal of the cellular phenotype in the premature
aging disease Hutchinson-Gilford progeria syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is a
childhood premature aging disease caused by a
spontaneous point mutation in lamin A (encoded
by LMNA), one of the major architectural elements of
the mammalian cell nucleus. The HGPS mutation
activates an aberrant cryptic splice site in
LMNA pre-mRNA, leading to synthesis of a truncated
lamin A protein and concomitant reduction in wild-type
lamin A. Fibroblasts from individuals with HGPS have
severe morphological abnormalities in nuclear envelope
structure. Here we show that the cellular disease
phenotype is reversible in cells from individuals with
HGPS. Introduction of wild-type lamin A protein does
not rescue the cellular disease symptoms. The mutant
LMNA mRNA and lamin A protein can be efficiently
eliminated by correction of the aberrant splicing
event using a modified oligonucleotide targeted
to the activated cryptic splice site. Upon splicing
correction, HGPS fibroblasts assume normal nuclear
morphology, the aberrant nuclear distribution and
cellular levels of lamina-associated proteins are
rescued, defects in heterochromatin-specific histone
modifications are corrected and proper expression of
several misregulated genes is reestablished. Our
results establish proof of principle for the
correction of the premature aging phenotype in
individuals with HGPS.
Update: further trawling through the email archive turns up notes of caution about getting too enthused about the above work, such as this:
Since I just spent some time reviewing the Lamin A research I'll make a
couple of comments (since the people who are hyping it do *not* have a long
background in the study of aging/gerontology).
1) Accelerated aging is *NOT* the inverse of longevity!
There are at least dozens, perhaps hundreds or thousands of ways you can
damage the "perfect" human genome and produce effects which cause one to die
prematurely. Werner's Syndrome and Hutchinson-Guilford Syndrome are the two
which most closely resemble "normal" aging. But George Martin wrote a paper
long ago (20 years?) detailing the characteristics of many diseases,
including Down's Syndrome, which have some symptoms which resemble aging.
What can be said with relative accuracy is "If you damage the WS gene or the
Lamin A gene in certain ways you will accumulate damage that resembles aging
more quickly than is normally the case."
2) Drugs or gene therapies which correct the defective Lamin A which causes
the accelerated aging in HGS will fix that specific genetic disease -- they
will do little or nothing to prevent "normal" aging. Animals lacking Lamin
A entirely *still* age and die (just animals on CR *still* age and die).
There has been a recent discussion about this on the GRG list which was
relatively informative. You should locate their archives (I don't have the
URL) if you want to go into the topic in greater depth.
Looks like this group is doing some very interesting work in the area of Progeria (basically these are premature aging diseases), with possible knock-on consequences for (anti-)aging in general...
Date: Tue, 2 May 2006 19:59:51 -0700 (PDT)
From: Doug Skrecky
Subject: mutated lamin A likely key driver of human
aging
[Farnesyltransferase inhibitors or lamin A specific
oligonucleotides offer the prospect of effective
treatments for Hutchinson-Gilford progeria. Since the
Lamin A defect responsible for this progeria also
plays a role in normal human aging, this raises the
interesting possibility of a significant increase in
the normal human lifespan in the near future.
Treatment of those suffering from progeria is expected
shortly.]
Science. 2006 Apr 27; [Epub ahead of print]
Lamin A-Dependent Nuclear Defects in Human Aging.
Scaffidi P, Misteli T.
National Cancer Institute, NIH, Bethesda, MD 20892
USA.
Mutations in the nuclear structural protein lamin A
cause the premature aging syndrome Hutchinson-Gilford
Progeria (HGPS). Whether lamin A plays any role in the
normal aging process is unknown. Here we show that the
same molecular mechanism responsible for HGPS is
active in healthy cells. Cell nuclei from old
individuals acquire similar defects as HGPS
patient cells including changes in histone
modifications and increased DNA damage. Age-related
nuclear defects are caused by sporadic use in
healthy individuals of the same cryptic splice site in
lamin A whose constitutive activation causes HGPS.
Inhibition of this splice site reverses the nuclear
defects associated with aging. These observations
implicate lamin A in physiological aging.
J Clin Invest. 2006 Mar;116(3):743-52.
Prelamin A and lamin A appear to be dispensable in the
nuclear lamina.
Lamin A and lamin C, both products of Lmna, are key
components of the nuclear lamina. In the mouse, a
deficiency in both lamin A and lamin C leads to slow
growth, muscle weakness, and death by 6 weeks of
age. Fibroblasts deficient in lamins A and C contain
misshapen and structurally weakened nuclei, and emerin
is mislocalized away from the nuclear envelope. The
physiologic rationale for the existence of the 2
different Lmna products lamin A and lamin C is
unclear, although several reports have suggested that
lamin A may have particularly important
functions, for example in the targeting of emerin and
lamin C to the nuclear envelope. Here we report the
development of lamin C-only mice (Lmna(LCO/LCO)),
which produce lamin C but no lamin A or prelamin A
(the precursor to lamin A). Lmna(LCO/LCO) mice were
entirely healthy, and Lmna(LCO/LCO) cells displayed
normal emerin targeting and exhibited only very
minimal alterations in nuclear shape and nuclear
deformability. Thus, at least in the mouse, prelamin A
and lamin A appear to be dispensable. Nevertheless, an
accumulation of farnesyl-prelamin A (as occurs with a
deficiency in the prelamin A processing enzyme
Zmpste24) caused dramatically misshapen nuclei and
progeria-like disease phenotypes. The apparent
dispensability of prelamin A suggested that
lamin A-related progeroid syndromes might be treated
with impunity by reducing prelamin A synthesis.
Remarkably, the presence of a single Lmna(LCO) allele
eliminated the nuclear shape abnormalities and
progeria-like disease phenotypes in Zmpste24-/- mice.
Moreover, treating Zmpste24-/- cells with a prelamin
A-specific antisense oligonucleotide reduced prelamin
A levels and significantly reduced the frequency of
misshapen nuclei. These studies suggest a new
therapeutic strategy for treating progeria and other
lamin A diseases.
Science. 2006 Mar 17;311(5767):1621-3. Epub 2006 Feb
16.
A protein farnesyltransferase inhibitor ameliorates
disease in a mouse model of progeria.
Progerias are rare genetic diseases characterized by
premature aging. Several progeroid disorders are
caused by mutations that lead to the accumulation of a
lipid-modified (farnesylated) form of prelamin A,
a protein that contributes to the structural
scaffolding for the cell nucleus. In progeria, the
accumulation of farnesyl-prelamin A disrupts
this scaffolding, leading to misshapen nuclei.
Previous studies have shown that farnesyltransferase
inhibitors (FTIs) reverse this cellular
abnormality. We tested the efficacy of an FTI
(ABT-100) in Zmpste24-deficient mice, a mouse model of
progeria. The FTI-treated mice exhibited improved body
weight, grip strength, bone integrity, and percent
survival at 20 weeks of age. These results suggest
that FTIs may have beneficial effects in humans with
progeria.
[Interesting that nuclear deformation is here
associated with proliferation defects. Some believe
this to be the major reason for escalating
age-associated mortality risks from vascular disease.]
Cell Biol Int. 2005 Dec;29(12):1032-7. Epub 2005 Nov
28.
Nuclear deformation characterizes Werner syndrome
cells.
Mutations in the lamin A gene have been shown, among
other defects, to give rise to Hutchinson-Gilford
progeria syndrome (HGPS) and to atypical Werner
syndrome (WS), both of which are progeroid disorders.
Here, we have investigated well-characterized WS
patient cell strains that are compound heterozygous
for mutations in the WRN gene. As in HGPS and in
atypical WS, we found nuclear deformations to be
characteristic of all cell strains studied. In WS
cells centrosome number, assembly of the nuclear
lamina and nuclear pore distribution occurred
normally. Furthermore, nuclear deformations were not
associated with a defect in lamin A expression. We
propose that nuclear deformation is a universal
characteristic of progeroid cells and may result from
slow cell cycle progression.
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16690-5.
Epub 2005 Nov 3.
Age-related changes of nuclear architecture in
Caenorhabditis elegans.
Mutations in lamins cause premature aging syndromes in
humans, including the Hutchinson-Gilford Progeria
Syndrome (HGPS) and Atypical Werner Syndrome. It has
been shown that HGPS cells in culture undergo
age-dependent progressive changes in nuclear
architecture. However, it is unknown whether similar
changes in nuclear architecture occur during
the normal aging process. We have observed that major
changes of nuclear architecture accompany
Caenorhabditis elegans aging. We found that the
nuclear architecture in most nonneuronal cell types
undergoes progressive and stochastic age-dependent
alterations, such as changes of nuclear shape and loss
of peripheral heterochromatin. Furthermore, we show
that the rate of these alterations is influenced by
the insulin/IGF-1 like signaling pathway and that
reducing the level of lamin and lamin-associated LEM
domain proteins leads to shortening of lifespan.
Our work not only provides evidence for changes of
nuclear architecture during the normal aging process
of a multicellular organism, but also suggests that
HGPS is likely a result of acceleration of the normal
aging process. Because the nucleus is vital for many
cellular functions, our studies raise the possibility
that the nucleus is a prominent focal point for
regulating aging.
Hum Genet. 2005 Dec;118(3-4):444-50. Epub 2005 Oct 6.
Correction of cellular phenotypes of
Hutchinson-Gilford Progeria cells by RNA interference.
The great majority of cases of the Hutchinson-Gilford
progeroid syndrome (HGPS) ("Progeria of Childhood'')
are caused by a single nucleotide mutation (1824 C->T)
in the LMNA gene which encodes lamin A and C, nuclear
intermediate filaments that are important components
of
the nuclear lamina. The resultant mutant protein
(Delta50 lamin A) is thought to act in a dominant
fashion. We exploited RNA interference technology to
suppress Delta50 lamin A expression, with the long
range goal of intervening in the pathogenesis of the
coronary artery atherosclerosis that typically leads
to the death of HGPS patients.
Short hairpin RNA (shRNA) constructs were designed to
target the mutated pre-spliced or mature LMNA mRNAs,
and were expressed in HGPS fibroblasts carrying the
1824 C->T mutations using lentiviruses. One of the
shRNAs targeted to the mutated mRNA reduced the
expression levels of Delta50 lamin A to 26% or lower.
The reduced expression was associated with
amelioration of abnormal nuclear morphology,
improvement of proliferative potential, and reduction
in the numbers of senescent cells. These findings
provide a rationale for potential gene therapy.
J Lipid Res. 2005 Dec;46(12):2531-58. Epub 2005 Oct 5.
Prelamin A, Zmpste24, misshapen cell nuclei, and
progeria--new evidence suggesting that protein
farnesylation could be important for disease
pathogenesis.
Prelamin A undergoes multistep processing to yield
lamin A, a structural protein of the nuclear lamina.
Prelamin A terminates with a CAAX motif, which
triggers farnesylation of a C-terminal cysteine (the
C of the CAAX motif), endoproteolytic release of the
last three amino acids (the AAX), and methylation of
the newly exposed farnesylcysteine residue. In
addition, prelamin A is cleaved a second time,
releasing 15 more residues from the C terminus
(including the farnesylcysteine methyl ester),
generating mature lamin A. This second cleavage step
is carried out by an endoplasmic reticulum membrane
protease, ZMPSTE24. Interest in the posttranslational
processing of prelamin A has increased with the
recognition that certain progeroid syndromes can be
caused by mutations that lead to an accumulation of
farnesyl-prelamin A. Recently, we showed that a key
cellular phenotype of these progeroid disorders,
misshapen cell nuclei, can be ameliorated by
inhibitors of protein farnesylation, suggesting a
potential strategy for treating these diseases. In
this
article, we review the posttranslational processing of
prelamin A, describe several mouse models for
progeroid syndromes, explain the mutations underlying
several human progeroid syndromes, and summarize
recent data showing that misshapen nuclei can be
ameliorated by treating cells with protein
farnesyltransferase inhibitors.
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14416-21.
Epub 2005 Sep 26.
Inhibiting farnesylation reverses the nuclear
morphology defect in a HeLa cell model for
Hutchinson-Gilford progeria syndrome.
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 and/or 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 and/or
other laminopathies due to Zmpste24 processing
defects.
[Blocking the manufacture of mutated lamin A with a
modified oligonucleotide reverses progeria in the test
tube as well.]
Nat Med. 2005 Apr;11(4):440-5. Epub 2005 Mar 6.
Reversal of the cellular phenotype in the premature
aging disease Hutchinson-Gilford progeria syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is a
childhood premature aging disease caused by a
spontaneous point mutation in lamin A (encoded
by LMNA), one of the major architectural elements of
the mammalian cell nucleus. The HGPS mutation
activates an aberrant cryptic splice site in
LMNA pre-mRNA, leading to synthesis of a truncated
lamin A protein and concomitant reduction in wild-type
lamin A. Fibroblasts from individuals with HGPS have
severe morphological abnormalities in nuclear envelope
structure. Here we show that the cellular disease
phenotype is reversible in cells from individuals with
HGPS. Introduction of wild-type lamin A protein does
not rescue the cellular disease symptoms. The mutant
LMNA mRNA and lamin A protein can be efficiently
eliminated by correction of the aberrant splicing
event using a modified oligonucleotide targeted
to the activated cryptic splice site. Upon splicing
correction, HGPS fibroblasts assume normal nuclear
morphology, the aberrant nuclear distribution and
cellular levels of lamina-associated proteins are
rescued, defects in heterochromatin-specific histone
modifications are corrected and proper expression of
several misregulated genes is reestablished. Our
results establish proof of principle for the
correction of the premature aging phenotype in
individuals with HGPS.
Update: further trawling through the email archive turns up notes of caution about getting too enthused about the above work, such as this:
Since I just spent some time reviewing the Lamin A research I'll make a
couple of comments (since the people who are hyping it do *not* have a long
background in the study of aging/gerontology).
1) Accelerated aging is *NOT* the inverse of longevity!
There are at least dozens, perhaps hundreds or thousands of ways you can
damage the "perfect" human genome and produce effects which cause one to die
prematurely. Werner's Syndrome and Hutchinson-Guilford Syndrome are the two
which most closely resemble "normal" aging. But George Martin wrote a paper
long ago (20 years?) detailing the characteristics of many diseases,
including Down's Syndrome, which have some symptoms which resemble aging.
What can be said with relative accuracy is "If you damage the WS gene or the
Lamin A gene in certain ways you will accumulate damage that resembles aging
more quickly than is normally the case."
2) Drugs or gene therapies which correct the defective Lamin A which causes
the accelerated aging in HGS will fix that specific genetic disease -- they
will do little or nothing to prevent "normal" aging. Animals lacking Lamin
A entirely *still* age and die (just animals on CR *still* age and die).
There has been a recent discussion about this on the GRG list which was
relatively informative. You should locate their archives (I don't have the
URL) if you want to go into the topic in greater depth.