CNS CHARACTERIZATION OF PRO/RE HYPERPROLINAEMIC MICE, A MODEL FOR A CANDIDATE SCHIZOPHRENIA SUSCEPTIBILITY GENE

Schizophrenia is a common and severe mental illness of though, emotion, and behavior that affects about 1% of the general population. It is a devastating disorder, probably unique to humans, affecting not only the sufferers but also their families. Over the past three decades, psychiatrists and geneticists have grappled with identifying the genetic determinants of schizophrenia, now universally thought to reside at multiple genes. Maria Karayiorgou’s laboratory, at Rockefeller University (New York), is focused on the genetics and neurobiology of schizophrenia. The main goal of the laboratory is looking for genes that affect these processes and whose mutations may contribute to schizophrenia susceptibility. Recently, the laboratory has identified on the human chromosome 22 a gene associated with schizophrenia. The gene encodes proline dehydrogenase, the first enzyme of proline catabolism. Proline is one of the 20 amino acids that constitute proteins. Moreover, proline is supposed to play an important role at the neuronal transmission level; nevertheless. its pathway and possible mechanism of action in the central nervous system is poorly understood. The Karayiorgou laboratory also created a mouse line reproducing the same mutation within the proline dehydrogenase gene found in human patients. The overall goal of my project will be to better understand the role of proline and proline dehydrogenase during normal brain development and function, and their mode of dysfunction in the disease, in these mutant animals. I am confident that the results arising from the project will have a strong impact in the understanding of the disease at molecular levels, suggesting possible new therapeutic strategies to tackle the disorder.