barani at mace.cc.purdue.edu
Thu Jan 19 19:07:19 EST 1995
Increase of deleted mitochondrial DNA in the striatum in
Parkinson's disease and senescence.
Ikebe S, Tanaka M, Ohno K, Sato W, Hattori K, Kondo T, Mizuno Y, Ozawa T
Department of Biomedical Chemistry, Faculty of Medicine, University of
Biochem. Biophys. Res. Commun. Aug 16 1990 170 (3) p1044-8.
A mutant mitochondrial DNA (mtDNA) with a 4,977-bp deletion was detected in
the parkinsonian brain by using the polymerase chain reaction. Although the
deleted mtDNA was detectable even in the brain of aged controls, the proportion
of deleted mtDNA to normal mtDNA in the striatum was higher in the parkinsonian
patients than in the controls. In both the parkinsonian patients and the aged
controls, the proportion was higher in the striatum than in the cerebral
cortex. These results indicate that age-related accumulation of deleted
mtDNA is accelerated in the parkinsonian striatum and suggest that the
deletion contributes to pathophysiological processes underlying
Hutchinson-Gilford progeria: familial occurrence.
Parkash H, Sidhu SS, Raghavan R, Deshmukh RN
Department of Dental Surgery, All-India Institute of Medical Sciences, New
Am J Med Genet Aug 1990 36 (4) p431-3
We report on 2 brothers with Hutchinson-Gilford progeria. These patients
have 2 unusual findings, i.e., marked resorption of the mandible along with
loss of teeth in the elder sib and prolonged survival. Both sibs are still
alive and active at the age of 32 and 24 years.
Altered regulation of platelet-derived growth factor A-chain and c-fos gene
expression in senescent progeria fibroblasts.
Winkles JA, O'Connor ML, Friesel R
Laboratory of Molecular Biology, Jerome H. Holland Laboratory for the
Biomedical Sciences, American Red Cross, Rockville, Maryland 20855.
J Cell Physiol Aug 1990 144 (2) p313-25
The study of human genetic disorders known as premature aging syndromes may
provide insight into the mechanisms of cellular senescence. These diseases are
clinically characterized by the premature onset and accelerated progression of
numerous features normally associated with human aging. Previous studies have
indicated that fibroblasts derived from premature aging syndrome patients have
in vitro growth properties similar to senescent fibroblasts from normal
individuals. As an initial approach to determine whether gene expression is
altered in premature aging syndrome fibroblasts, RNA was prepared from various
cell strains and used for gel blot hybridization experiments. Although normal
fibroblasts only express platelet-derived growth factor (PDGF) A-chain mRNA for
a brief period following mitogenic stimulation, one strain of Hutchinson-
Gilford (progeria) syndrome fibroblasts, AG3513, constitutively expresses PDGF
A-chain mRNA and PDGF-AA homodimers. The PDGF A-chain gene does not appear to
be amplified or rearranged in these fibroblasts. AG3513 progeria fibroblasts
have properties characteristic of senescent cells, including an altered
morphology and a diminished mitogenic response to growth promoters. The
diminished response of AG3513 progeria fibroblasts to PDGF stimulation was
examined in some detail. Studies using 125I-PDGF-BB, which binds with high
affinity to both A- and B-type PDGF receptors, indicate that normal and AG3513
progeria fibroblasts have a similar number of PDGF receptors. Although
receptor autophosphorylation occurs normally in PDGF-stimulated AG3513
progeria fibroblasts, c-fos mRNA induction does not. The senescent phenotype
of AG3513 fibroblasts is probably unrelated to their constitutive PDGF A-chain
gene expression, further studies are necessary in order to directly address
this issue. Also, additional analysis of this progeria fibroblast strain may
provide information on the control of mitogen-inducible gene expression in
Does progeria provide the best model of accelerated ageing in humans?
Mills RG, Weiss AS
Department of Biochemistry, University of Sydney, Australia.
Gerontology 1990 36 (2) p84-98
Studies of the causes of ageing are often obscured by the complexity of this
phenomenon, hindering investigations in this area. In particular, the variable
characteristics of ageing complicate analysis at a molecular level. It is
proposed that to gain insight into ageing, the problem must first be simplified
by restricting studies to an aspect of the ageing processes. It is suggested
that progeria, which presents a less complicated etiology and phenotype than
other accelerated ageing diseases, allows research to focus on a regulation
site involved in development and ageing.
Ophthalmological aspects in patients with Werner's syndrome.
Department of Ophthalmology, University of Erlangen-Nurnberg, F.R.G.
Arch Gerontol Geriatr Nov-Dec 1989 9 (3) p263-70
In ten of 18 eyes from nine patients with Werner's syndrome, cataract surgery
was complicated by wound dehiscence and its consequences: peripheral anterior
synechiae (4), secondary epiretinal gliosis (4), cystoid macular edema (3) in
the framework of Hruby-Irvine-Gass syndrome, unplanned filtering bleb (2), and
post-operative anterior ischemic optic neuropathy (1). Additionally, corneal
endothelial decompensation occurred in eight eyes. In view of the fibroblasts'
reduced growth potential, we suggest small surgical incisions, extracapsular
cataract surgery using phacoemulsification, intraocular irrigation solutions
protecting corneal endothelium, nonabsorbable single knot sutures not removed
before 1 year after surgery, and no local or systemic use of cortisone.
Bilateral spontaneous dislocated lenses, retinal vasculitis and progeria-like
Sharir M, Ragenbogen L
Goldschlager Eye Institute, Sheba Medical Center, Tel Hashomer, Israel.
Metab Pediatr Syst Ophthalmol 1990 13 (1) p5-9
Findings are reported for a 70-year-old man with a progeria-like syndrome
consisting of premature aging (per history), diffuse wasting, skin atrophy,
disseminated skeletal osteoporosis (documented for at least 25 years),
especially in the vertebral column and metacarpal joints with short stature,
beaked nose and high-pitched voice, The ocular findings include: spontaneous
bilateral dislocation of spherophakic mature cataracts into the vitreous
together with bilateral retinal vasculitis, characterized by venous congestion,
tortuosity and occlusion, To the best of our knowledge, there is no case report
with all the above features in one person, Hence, the differential diagnosis
will also be discussed.
Clonal structural chromosomal rearrangements in lymphocytes of four patients
with Werner's syndrome.
Scappaticci S, Forabosco A, Borroni G, Orecchia G, Fraccaro M
Biologia Generale e Genetica Medica, Universita di Pavia, Italia.
Ann Genet 1990 33 (1) p5-8
Multiple numerical and structural chromosome abnormalities were found in
cultured lymphocytes of four patients with Werner's syndrome. The proportion
of metaphases with structural and/or numerical aberrations varied from 30 to
44% and several of them were clonal. These results confirm definitively that
Werner's syndrome is a chromosome rearrangement syndrome and that these non-
constitutional chromosome changes are not exclusive of cultured fibroblasts but
present also in lymphocytes.
Ultraviolet light-induced DNA damage in transcribed sequences: no change in
repair with age.
Kunisada T, Miller CD, Schneider EL
Laboratory of Molecular Genetics, National Institute on Aging, Baltimore, MD
Mutat Res Mar 1990 237 (2) p75-81
We studied the repair of a plasmid vector containing the chloramphenicol
acetyltransferase (CAT) gene by treating the plasmid with UV light and then
transfecting this plasmid into fibroblasts from human fetal lung (in vitro
aging) and into primary cultured fibroblasts from rat lung and skin. This
methodology allows us to examine the repair of specific transcribed DNA
sequences. There was no age-related change in the repair of UV damage in these
cells. Rat embryo fibroblasts at different passages transfected with the
plasmid also revealed no significant alteration in UV repair as a function of
Are transposons a cause of ageing?
Molecular Sciences Group, Peter MacCallum Cancer Institute, Melbourne, Vic.,
Mutat Res Mar 1990 237 (2) p59-63
A hypothesis for ageing is proposed based on the properties of transposons.
During the process of transposition, one copy of the DNA sequence generally
remains at the same position while the other copy moves to another location in
the genome. In this manner the DNA sequence of the transposon is effectively
duplicated. With time the number of transposons increases exponentially and
since in their new location they can inactivate an essential gene, they will
eventually kill a cell line or organism. Thus transposons could be a cause of
ageing. This hypothesis is attractive because it can explain many of the
properties of senescent cells. Other processes capable of DNA self-duplication
(e.g., reverse transcription) could also contribute to the increase in
transposable DNA sequences.
Sister chromatid exchange and proliferation pattern in lymphocytes from
newborns, elderly subjects and in premature aging syndromes.
Melaragno MI, Smith M de A
Disciplina de Genetica, Escola Paulista de Medicina, Sao Paulo SP, Brazil.
Mech Ageing Dev May 15 1990 54 (1) p43-53
Sister chromatid exchange (SCE) frequency and cell proliferation were
examined in lymphocyte cultures from a group of newborns, a group of elderly
subjects and from patients with syndromes who exhibit progeriform
characteristics (progeria, Cockayne syndrome, Rothmund-Thomson syndrome and
Christ-Siemens-Touraine syndrome) by using the bromodeoxyuridine incorporation
differential staining technique. We observed a significantly increase in basal
SCE frequency and a less intensive cell proliferation in cultures from elderly
subjects than from newborns, as shown by the significant increase in percentage
of cells in first generation simultaneous with a reduction of cells in more
advanced generations. Lymphocyte cultures from each one of the patients
studied also showed a decreased cell proliferation in relation to their
respective control and to newborn cultures. Each of these syndromes showed
higher baseline SCE levels than the control and than the newborn and elderly
groups. Only the patient with progeria showed values similar to those for the
elderly group. Thus, in addition to showing clinical characteristics similar
to those observed during the normal aging process, these progeriform syndromes
also show cytogenetic characteristics similar to those of older individuals.
Mitochondrial mutations may increase oxidative stress: implications for
carcinogenesis and aging?
Bandy B, Davison AJ
Bioenergetics Research Laboratory, School of Kinesiology, Simon Fraser
University, Burnaby, B.C., Canada.
Free Radic Biol Med 1990 8 (6) p523-39
The sensitivity of mitochondrial DNA to damage by mutagens predisposes
mitochondria to injury on exposure of cells to genotoxins or oxidative stress.
Damage to the mitochondrial genome causing mutations or loss of mitochondrial
gene products, or to some nuclear genes encoding mitochondrial membrane
proteins, may accelerate release of reactive species of oxygen. Such aberrant
mitochondria may contribute to cellular aging and promotion of cancer.
Inheritable abnormal lipoprotein metabolism in Werner's syndrome similar to
Mori S, Yokote K, Morisaki N, Saito Y, Yoshida S
Second Department of Internal Medicine, School of Medicine, Chiba University,
Eur J Clin Invest Apr 1990 20 (2) p137-42
Studies were made on the abnormality of lipoprotein metabolism and its cause
in 10 patients with Werner's syndrome. Seven of the 10 patients had
hypercholesterolaemia (above 250 mg dl-1). Six of the seven patients with
hypercholesterolaemia had thickened Achilles' tendons (greater than 9 mm). A
significant positive correlation (P less than 0.01) was found between the serum
total cholesterol levels and the thickness of Achilles' tendons in these 10
patients, suggesting that the substance precipitated in the thickened tendons
is derived from serum cholesterol. Some first-degree relatives of three
patients with both hypercholesterolaemia and xanthoma-like thickening of
Achilles' tendons also suffered from hypercholesterolaemia. Moreover, the low
density lipoprotein (LDL) receptor activities in peripheral lymphocytes of five
patients with both hypercholesterolaemia and xanthoma-like tendons were
significantly (P less than 0.001) lower than those of controls, whereas the LDL
receptor activities of two patients without hypercholesterolaemia were almost
the same as those of controls. These findings suggest that, at least these
five patients with lower lymphocyte LDL receptor activities, and probably
another patient with both hypercholesterolaemia and xanthoma-like thickening of
Achilles' tendons suffered from familial hypercholesterolaemia (FH). If this
is the case, this high frequency of association of Werner's syndrome with FH
(in six of 10 patients) suggests some relationship between these two diseases.
Recessively inherited deficiencies predisposing to cancer.
Department of Research, University Clinics, Kantonsspital, Basel,
Anticancer Res Mar-Apr 1990 10 (2B) p513-8
The genetic factors involved in the multistep process of carcinogenesis can
be divided at least into two major categories: 1. Mutated or lost genes, which
may directly represent one step in the sequential process (tumour suppressor
genes), inheritance of one tumour suppressor gene causes dominant expression of
the carcinogenic phenotype (the dominant inheritance is described in the
accompanying paper), 2. Other genes, which lead to conditions that favour the
development of cancer and generally are inherited in a recessive fashion, they
are the subject of this paper. Autosomal recessively inherited diseases, such
as xeroderma pigmentosum, ataxia-telangiectasia, Bloom's syndrome and Fanconi's
anaemia display increased genome instability (chromosomal fragility and/or DNA-
repair deficiencies) and are associated in the homozygote and probably also in
the heterozygote state with defined malignancies. Neoplasms particularly of
the lymphoreticular system frequently occur in patients with genetically
determined immunodeficiencies (e.g. severe combined immune deficiency or
Wiskott-Aldrich syndrome). People differ due to their individual genetic
constitution in their responses to various classes of carcinogens such as
physical and chemical agents, to dietary habits, as well as to viruses.
Furthermore, tumours are often found in patients displaying premature aging
(e.g. Werner's syndrome). In addition, several metabolic abnormalities such
as genetic syndromes featuring chronic liver disease, but also many other
inherited metabolic conditions have cancer as a regular or frequent
Growth properties and in vitro life span of Alzheimer disease and Down
syndrome fibroblasts. A blind study.
Carmeliet G, Hauman R, Dom R, David G, Fryns JP, Van den Berghe H, Cassiman
Center for Human Genetics, University of Leuven, Belgium.
Mech Ageing Dev Mar 31 1990 53 (1) p17-33
A blind study was set up to examine the in vitro growth characteristics of
skin fibroblasts from 2 individuals with and 9 at risk for familial Alzheimer
disease, 4 individuals with sporadic Alzheimer disease, 18 with Down syndrome
as well as 5 younger and 6 older controls. Several variables (biopsy size,
number of explants, medium, passage procedure) were standardized. Two growth
characteristics were examined quantitatively: (i) the actual in vitro
replicating life span was determined by counting the number of cells plated the
previous week at 500,000 cells/flask (cumulative population doublings), and
(ii) the growth potential was examined by a colony size distribution assay. A
difference from the age-matched controls in the growth characteristics of skin
fibroblasts was only observed for two patients with and one older individual at
risk for familial Alzheimer disease. The growth properties of skin fibroblast
cultures from patients with sporadic Alzheimer disease or Down syndrome were
not at variance with their age-matched controls. The decrease in the growth
potential observed in the familial Alzheimer disease fibroblasts is however
modest and needs confirmation. It is clear that the growth properties of skin
fibroblasts, as examined in this study, do not provide a good marker for any
form of Alzheimer disease, nor do they provide an appropriate in vitro system
to study factors which may contribute to the etiopathogenesis of Alzheimer
disease or Down syndrome.
Establishment of immortalized primate epithelial cells with sub-genomic EBV
Karran L, Teo CG, King D, Hitt MM, Gao YN, Wedderburn N, Griffin BE
Department of Virology, Royal Postgraduate Medical School, Hammersmith
Hospital, London, UK.
Int J Cancer Apr 15 1990 45 (4) p763-72
The genetic information in a sub-fragment of EBV DNA, designated p31
(containing less than a quarter of the viral genome and derived from a
recombinant DNA cosmid library) allows epithelial cells from primary monkey and
human kidney cultures to escape senescence under standard tissue culture
conditions. A number of epithelial cell lines, designated M1/31, 483/31,
199/31 and HK/31, have been established and characterized following
transfection of primary cells with p31 DNA. They share many properties,
although morphologically they are not all identical. The cultures are
immortalized but not fully transformed or tumorigenic. They appear to be
phenotypically stable, although DNA hybridization studies indicate that
genotypic alterations, including amplification, occur subsequent to
transfection with p31 DNA and the establishment of a continuously proliferating
epithelium. All cell lines consistently express high levels of cytokeratin 18
and varying amounts of cytokeratin 7, demonstrating their epithelial origin.
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