DESCRIPTION (application abstract): The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are inherited pediatric neurodegenerative diseases. The aim of this application is to exploit neuron cultures developed from an ovine model as an in vitro model of human disease and use it, in combination with whole animal studies, to study the mechanism of neurodegeneration and explore possible therapies. The NCLs are characterized by profound neurodegeneration and the intracellular accumulation of subunit c of mitochondrial ATP synthase. Cortical neuronal cultures have been established from affected sheep and storage body accumulation observed in cultured cells. This investigation will optimize these neuron Cultures as a model of the in situ pathology. The mechanism of neurodegeneration will be studied in them. Specific hypotheses to be tested are that subunit c storage is directly related to neurodegeneration, that a disruption in the endosome-lysosome pathway is central to the neurodegeneration and that accumulation of subunit c results in over-activity of an oligomeric subunit c ionpore in the neuronal plasma membrane. The role of apoptosis and excitotoxicity will be examined and the efficacy of IGF1 and other growth factors that might overcome neurodegeneration tested. Chimeric normal/affected sheep will be generated to delineate the possibilities for gene and enzyme therapy. The clinical course of disease will be monitored in affected sheep transgenically overexpressing IGF1 in brain, to determine if this ameliorates the development of symptoms. Possible therapies will be tested in whole animal experiments. Results will be relevant to understanding the pathobiology of the NCLs and will test the likelihood of benefits of possible treatments. Findings will also be relevant to understanding other protein storing neurodegenerative diseases, such as Alzheimer's disease.