Dr. Tagle's research goal is to understand the molecular mechanisms that underlie neuronal death and neuronal survival. Neuronal death has long been recognized as a normal feature of nervous system maturation where more than 50% of the neurons acquired du ring development undergo programmed cell death. Subtle nerve cell damage and loss continues as a normal process of aging. On the other hand, premature and selective loss of neurons are also a key feature of pathologies in the adult nervous system, incl uding Huntington's disease, Alzheimer's disease, Parkinson's disease, epilepsy, and other motor neuron disorders. The causes of these neurodegenerative diseases remains largely unknown and the identification of responsible genes provide an initial step to wards understanding the molecular processes that have gone awry in these disorders. A number of mechanisms have been proposed that can lead to neuronal death, including excitotoxicity (involving excess glutamatergic activation and subsequent calcium infl ux), oxidative stress, endosome/lysosome aggregation, defects in mitochondrial bioenergetics, and more recently, polyglutamine toxicity. Understanding the pathophysiology of diseases of the nervous system is an important focus of the program. Through the generation of animal and cellular models, a better understanding of the molecular events and interacting pathways leading to neuronal death can be obtained that will allow the development of strategies to delay or prevent the death of neurons in injured or degenerating brain.

Part of the lab's research in the Molecular Neurogenetics Section of the Genetics and Molecular Biology Branch at NHGRI entails the identification and characterization of genes involved in inherited neurodegenerative disorders. Through productive collabo rations, members of the laboratory have been successful in the identification by positional cloning approaches of at least three genes involved in neurodegeneration. These include the genes responsible for Huntington's disease (HD), ataxia-telangiectasia (A-T), and Niemann-Pick type C disease (NPC). These genes and their protein products are being utilized to generate molecular tools and reagents that allows us to provide better diagnosis for these diseases as well as understand their cellular function s and protein partners in both normal and mutated states. Clinically relevant models are being developed and used both as tools to test mechanistic hypotheses and as a means to develop clinically useful neuroprotective/neuroregenerative interventions.

In addition to standard molecular biology and recombinant DNA techniques, they employ a variety of techniques including histochemistry, immunocytochemistry, in situ hybridization, and cell culture utilizing primary cultures and neuronal cell lines. Physi ological, behavioral and histopathological analyses are used to assess neurodegeneration in animal models. As an adjunct to therapeutic approaches, QTL mapping and genetic crosses can be useful for the identification of other genes and gene products that can modify the effects of the disease locus.