NOS1AP Interacts with α-Synuclein and Aggregates in Yeast and Mammalian Cells

The NOS1AP gene encodes a cytosolic protein that binds to the signaling cascade component neuronal nitric oxide synthase (nNOS). It is associated with many different disorders, such as schizophrenia, post-traumatic stress disorder, autism, cardiovascular disorders, and breast cancer. The NOS1AP (also known as CAPON) protein mediates signaling within a complex which includes the NMDA receptor, PSD-95, and nNOS. This adapter protein is involved in neuronal nitric oxide (NO) synthesis regulation via its association with nNOS (NOS1). Our bioinformatics analysis revealed NOS1AP as an aggregation-prone protein, interacting with α-synuclein. Further investigation showed that NOS1AP forms detergent-resistant non-amyloid aggregates when overproduced. Overexpression of NOS1AP was found in rat models for nervous system injury as well as in schizophrenia patients. Thus, we can assume for the first time that the molecular mechanisms underlying these disorders include misfolding and aggregation of NOS1AP. We show that NOS1AP interacts with α-synuclein, allowing us to suggest that this protein may be implicated in the development of synucleinopathies and that its aggregation may explain the relationship between Parkinson’s disease and schizophrenia.