Project Summary

Gabriel A. Vargas, M.D., Ph.D. (Young Investigator 2005) of the University of California at San Francisco, proposes studying a protein, called NPC1, which interacts with the dopamine D1 receptor, which is believed to be involved in the neurocognitive deficits found in schizophrenia. Recent work has found a dysregulation in the number of D1Rs in the frontal cortex of schizophrenic patients. Other work has identified a number of dopamine receptor interacting proteins (DRIPs) that are involved in D1R regulation. Some of these DRIPs are upregulated in schizophrenia. By understanding dopamine receptor regulation by interacting proteins it may be possible to try to correct functioning of the dopaminergic system, which is abnormal in many neuropsychiatric diseases. To identify proteins that interact with the D1R, Dr. Vargas employed the yeast two-hybrid screen using the cytoplasmic tail of the D1R as bait and a human cDNA brain library as prey. One positive clone encoded NPC1, a protein involved in the human genetic disease Niemann-Pick Type C (NPC), a neurodegenerative disorder. Interestingly, mild cases of this disorder can present initially with only psychiatric symptoms, such as paranoid ideation and auditory hallucinations. This proposal aims to biochemically identify the interacting domains of NPC 1 and D1R and to study the functional consequences of this interaction on Dl receptor activity using cell lines and primary neuronal cultures. Findings should provide insight into a novel mechanism of dopamine receptor regulation and should also provide clues about the psychiatric manifestations of NPC.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia\Neurodegeneration

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