Schizophrenia and other major
mental illnesses result from a complex interplay of genetic and environmental factors. We previously identified a mutation in NPAS3 that results in a
valine to
isoleucine (V304I) amino acid substitution segregating with
schizophrenia in a small family. The
amino acid change occurs in a potentially critical region for
protein function. Furthermore, the same amino acid substitution in
proteins related to familial
Alzheimer's disease and
transthyretin amyloidosis has been associated with
protein aggregation. In this study, we demonstrate that NPAS3 is prone to aggregation, and that the V304I mutation in NPAS3 increases this propensity in both bacterial and mammalian expression systems. We also show that NPAS3-V304I reduces soluble endogenous NPAS3, and increases insoluble endogenous NPAS3 and leads to alteration of transcriptional activity. These results suggest that
protein aggregation, potentially leading to cell dysfunction via a loss of
protein function through sequestration, may contribute to the pathogenesis of
schizophrenia and other forms of
mental illness. Further exploration of the mechanisms leading to abnormal
protein quality control could lead to new therapeutic targets.