Download Current Status of the Evolutionary Theory of Why We Age and its

A Proposal for an Ambitious Program of Research on
the Genetic Basis for Elite Human Aging
George M. Martin, M.D.
Depts. of Pathology and Genome Sciences,
University of Washington, Seattle, WA USA
[email protected]
Genetic research using model organisms such as C. elegans, D.
melanogaster and M. domesticus has until now focused upon a single
phenotype – life span. While such experiments have provided us with
major advances – notably evidence of the first biochemical genetic
“public” mechanism for the modulation of length of life, the paucity of
information on the physiology of aging in these model organisms
(especially for the case of worms and flies) have precluded a genetic
analysis of variations in rates of change of specific physiological functions.
Human geneticists are in a position to carry out such studies in our own
species, given suitable collaborations with physiologists and bioengineers
and substantial long-term financial support from governmental and private
sources. We shall discuss such a program of research, one that has the
potential to discover the molecular basis of exceptionally robust retention
of structure and function in aging populations of human subjects (“elite”
aging). Our lecture will provide an update on a previous online publication
on this subject (GM Martin, Help Wanted: Physiologists for Research on
Aging, Sci. Aging Knowl. Environ., 6 March 2002 Vol. 2002, Issue 9, p.
vp2 [DOI: 10.1126/sageke.2002.9.vp2].
A Drosophila Model of Autosomal Recessive Juvenile
Parkinsonism
Kyoung Sang Cho, Ph.D.
Department of Biological Sciences, Konkuk University, Seoul 143-701, Korea
[email protected]
Parkinson"s disease (PD) is the second most common neurodegenerative
disease. The symptoms of PD include rigidity, tremor, bradykinesia of the
limbs, and postural instability. These symptoms result primarily from a
deficiency of dopamine caused by selective degeneration of dopaminergic
neurons. Parkin, the protein deficient in autosomal recessive juvenile
parkinsonism (AR-JP), functions as an E3 ubiquitin ligase. In the present
study, I isolated the Drosophila parkin (Dparkin) gene and its mutants. The
Dparkin protein is highly conserved with a human counterpart and
possesses E3 ubiquitin ligase activity. Dparkin loss-of-function mutants
displayed an erect wing phenotype and Parkinson’s disease-like symptoms
such as locomotor defects and dopaminergic neurodegeneration.
Intriguingly, the dopaminergic neurodegeneration occurred through
caspase-dependent apoptosis, which was highly correlated with the
activation of JNK. Collectively, these results suggest that
neurodegeneration in Dparkin mutants and perhaps AR-JP patients is due to
the loss of Parkin-dependent negative regulation of JNK activity and
apoptosis. Additionally, I will present the result of proteomic analysis of
Dparkin mutant brain.
Cognitive Dysfunction Induced by Chronic Restraint
Stress in Ovariectomized Animals
Kiyofumi Yamada, Ph.D.
Laboratory of Neuropsychopharmacology, Graduate School of Natural Science
and Technology, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan
[email protected]
Several lines of evidence suggest that hormonal changes after menopause
may play an important role in the incidence of cognitive dysfunction, and
also in the development of Alzheimer's disease. In this study, we
investigated the effect of estrogen on cognitive function in rats under
different stress environment. Female rats were divided into four groups:
two groups were ovariectomized (OVX) and two were sham-operated. One
group each of OVX and sham rats was kept in a normal environment, and
the other groups were assigned to a daily restraint stress (6 h/day) for 21
days from two months after the operation. Following the stress period,
subjects were tested for performance in novel object recognition test and
then used for morphological and neurochemical analyses. The OVX plus
stress (OVX/stress) group showed a significant impairment of recognition
of novel objects, compared with the other groups. The OVX/stress group
also showed a marked decrease in the number of pyramidal cells of the
CA3 region and levels of brain-derived neurotrophic factor (BDNF) mRNA
in the hippocampus. We further examined the effect of estrogen
replacement against cognitive dysfunction in OVX/stress rats. Vehicle or
17-estradiol (E2) was subcutaneously administered to OVX/stress rats for
4 weeks before the stress period through an implantable osmotic pump.
Chronic E2 treatment improved the cognitive, morphological and
neurochemical impairments relative to vehicle group. These data have
important implications for cognition enhancing effect of estrogen
replacement therapy in postmenopausal women.
The Role of NFB42 in Neuronal Latency of Herpes
Simplex Virus Type 1
Chi-Yong Eom, Ph.D.
Metabolome Analysis Team, Korea Basic Science Institute,
Anam-dong, Seongbuk-gu, Seoul 136-701, Korea
[email protected]
We have identified cellular proteins that interact with the herpes simplex
virus type 1 (HSV-1) origin-binding protein (UL9 protein) by using the
yeast two-hybrid system. We identified NFB42, an F-box protein that is
highly enriched in the nervous system, as a binding partner for the herpes
simplex virus 1 UL9 protein. We showed that coexpression of NFB42 and
UL9 genes leads to a significant decrease in the level of UL9 protein.
Treatment with the 26S-proteasome inhibitor MG132 restores the UL9
protein to normal levels. We have observed also that the UL9 protein is
ubiquitinated in vivo. The interaction between NFB42 and the UL9 protein
is dependent upon phosphorylation of the UL9 protein. We have found that
HSV-1 infection promotes the shuttling of NFB42 between the cytosol and
the nucleus, permitting NFB42 to bind to the phosphorylated UL9 protein.
This interaction mediates the export of the UL9 protein from the nucleus to
the cytosol, leading to its ubiquitination and degradation via the 26S
proteasome. Because the intranuclear localization of the UL9 protein, along
with other viral and cellular factors, is an essential step in viral DNA
replication, degradation of the UL9 protein in neurons by means of nuclear
export through its specific interaction with NFB42 may prevent active
replication and promote neuronal latency of HSV-1.