We study neuropsychiatric disorders, using a wide range of techniques, with an ultimate goal of illuminating normal human brain function. Huntington's disease (HD) and Parkinson's disease (PD) are models which may provide methods for approaching the more complex psychiatric disorders such as schizophrenia. HD is an autosomal dominant, progressive, fatal neurodegenerative disorder causing abnormality of movements, thoughts and emotions, with degeneration in the striatum of the basal ganglia. An expanding CAG repeat coding for polyglutamine in the Huntington protein causes altered conformation of the protein, aggregation and the formation of intranuclear neuronal inclusions. We have suggested that the major source of cell toxicity may be an oligomeric soluble aggregate with a compact beta sheet conformation. We use biophysical and biochemical techniques, cell models, and mouse models in order to better understand these processes, and provide targets for development of rational therapeutics. More recently we have focused on molecular pathogenesis of Parkinson's disease. We have studied alpha-synuclein, the first identified cause of genetic PD, and more recently Leucine Repeat rich Kinase 2 (LRRK2), another autosomal dominant form. Schizophrenia has long been believed to be a subtle disorder of neuronal development. Disrupted in Schizophrenia 1 (DISC1) was previously identified as being interrupted by a chromosomal dislocation, which strikingly segregates with schizophrenia and other major mental illness in a large pedigree in Scotland. We have preliminary data indicating that transgenic mouse models over-expressing the predicted mutant DISC1 protein product have subtle abnormalities of neurite outgrowth and behavior. Thus, the hope is that by using similar cellular and molecular techniques which have been successful in the neurodegenerative diseases, we can better understand psychiatric disorders such as schizophrenia.