Genetical interaction of DISC1 and autism spectrum disorder genes in fruit fly

Pandey Himani, Kazuki Kurita, Yuko Yoshimura, and Katsuo Furukubo-Tokunaga

Graduate School of Life and Environmental Sciences, University of Tsukuba, Japan

Schizophrenia, a debilitating mental illness with a very high lifetime risk, is characterized by positive symptoms (e.g. - delusions and hallucination), negative symptoms (e.g. affective flattering, apathy and social withdrawal) and cognitive symptoms (e.g. memory deficits, attentional deficits). Psychiatric studies in the past decades reveled that schizophrenia and other mental disorders are caused by a combination of multiple genetic risk factors and environmental insults. Although its molecular etiology remains still unclear, genetic analysis of the affected patients identify a large number of risk factor genes for schizophrenia and related disorders. Among them, Disrupted-in-Schizophrenia-1 (DISC1), originally identified at the breakpoint of a chromosome (1;11)(q42.1; q14.3) translocation, is a highly potent susceptibility gene for both schizophrenia and affective disorders. To analyze the molecular genetic mechanisms between the risk genes of diverse disorders, we have introduced the human DISC1 gene into fruit flies (Drosophila melanogaster) and analyzed its functions in the developing nervous system. Here, I present our data that focuses on the alteration of synaptic structures caused by overexpressing the human DISC1 gene in the Drosophila nuromuscular junctions. In addition, we analyzed epistatic genetic interactions between DISC1 and other susceptibility genes using the fly system, and found that DISC1 interacts with genes of autism spectrum disorders. This study allows us to understand how multiple mutations in diverse risk genes affect neurodevelopment and functions. Thus we can relate the outcome of our study to analyze the underlying epistatic interactions in the molecular etiology of the human mental diseases.