DISC1-cytomegalovirus: An example of gene-environment interaction potentially implicated in mental illness.

摘要

DISC1 is a susceptibility factor for mental illnesses including schizophrenia (SZ) and autism. DISC1 was disrupted as a result of a balanced translocation involving chromosomes 1 & 11 in a Scottish family with a history of SZ and other mental illnesses. Subsequent studies have shown that DISC1 is a neurodevelopmental protein that regulates neuronal progenitor cells proliferation, neuronal cell migration and dendritic arborization. However, there are many evidences suggesting that SZ is not a purely genetic disorder and that environmental factors may also play a role in the pathogenesis of SZ. Epidemiological studies have suggested that viruses such as CMV and HSV may be implicated in some cases of SZ. Other human studies have reported an association between CMV infection and autism. The mechanisms by which these viruses could lead to mental illnesses are poorly understood. This thesis will focus on CMV and attempts to delineate a pathway that could potentially underly CMV induced mental illnesses. Chapter I proposes an approach to generate animal models to study the role of gene-environment interaction in the pathogenesis of SZ. Chapter II gives an example of gene-environment interaction that could potentially be implicated in CMV induced mental illnesses. We show that CMV can interfere with the function of the nuclear pool of DISC1 and the outcome is impaired proliferation of neuronal progenitor cells in the developing cortex. In Chapter III, we present data suggesting that CMV induced impaired neuronal migration occur at least in part via disruption of PML-DISC1 interaction.