DESCRIPTION (Adapted from the application): Neurodegenerative diseases exact a massive toll on human and health care resources. They also pose the fundamental question of the mechanisms underlying selective degeneration of particular neuronal populations. Recent identification of the genes involved in several major neurodegenerative disorders, including Huntington's disease and Alzheimer's disease, represent major advances, but have not yet revealed how the encoded proteins produce cell death. Additional components of the neurodegenerative pathway must be identified. The applicants propose to use Drosophila as a model system to identify proteins required for neuronal degeneration. Both Huntington's disease and Alzheimer s disease are dominantly inherited neurodegenerative disorders most likely produced by toxic actions of the encoded gene products. Appropriate forms of both proteins will be expressed in Drosophila using the GAL4 system that facilitates transgene expression in a variety of defined tissue-specific and temporal patterns. The anatomic and behavioral abnormalities resulting from expression of the human transgenes will be characterized, and a phenotype suitable for generating second site suppressors and enhancers will be defined. Flies will then be mutagenized and genetic modifiers isolated. Mammalian homologues of these Drosophila modifiers will be human disease gene candidates and likely components of mammalian neurodegenerative pathways. The ability of many Drosophila proteins, including several discussed in the current application, to substitute functionally for their mammalian counterparts, suggests close analogies between the two systems. Even seemingly highly unique processes such as hindbrain compartmentalization and learning and memory show remarkable similarities. The basic cell biology of neurodegeneration should prove no exception. The applicant is an M.D./Ph.D. who will have completed a residency in anatomic pathology and subspecialty training in neuropathology prior to the proposed start date. She also holds a doctoral degree in neurobiology. The research will be carried out in a Drosophila laboratory group within the Harvard Medical School. A co-sponsor expert in human molecular genetics and neurodegenerative diseases has been selected to complement the primary laboratory's expertise in Drosophila molecular genetics and development.