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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.