Disrupted-In-Schizophrenia-1 (DISC1) is a susceptibility gene for major mental illnesses, such as depression and schizophrenia. DISC1 interacts with a number of proteins, which have a myriad of roles in neurobiological processes that may underlie pathophysiology of mental illnesses. FEZ1 is one of the DISC1 binding proteins, but how this protein may be relevant to the pathophysiology of mental illnesses is not known. In this study, we used Drosophila and mouse model systems to characterize molecular and cell biological roles of FEZ1. FEZ1 null mutants in Drosophila larvae showed defects in axonal transport of several cargoes, including synaptic vesicles and autophagosomes. FEZ1 binds the motor protein, kinesin heavy chain, and functions as a motor adaptor protein, linking kinesin to its cargo. We have evidence that DISC1 and FEZ1 function together in axonal transport, and psychotropic agents disrupted the interaction between the FEZ1-containing motor complex and cargoes. In addition, a mood stabilizer lithium upregulated the interaction of FEZ1 and the cargoes, through phosphorylation of FEZ1 Ser-58, and normalized the psychostimulant-induced hyperlocomotion in FEZ1-KO mice. Through the present study, we now propose a novel working hypothesis that aberrant axonal transport could be a hallmark of psychiatric manifestation that might be used as a neurobiological marker for some mental illnesses.

This work was supported in part by Takeda Pharm. Co. Ltd. (to TT)