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NPAS3 aggregation, implicated in schizophrenia, is common in post mortem brain samples and can be induced by oxidative stress in neuroblastoma cells

Chronic mental illnesses are complex conditions, that include various genetic and non-genetic aspects. Recent research suggests the existence of insoluble protein aggregates in the brains of patients. The onset of protein aggregation could be due to disruptions in protein homeostasis or incorrect protein folding, similar to neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases [1]. One of the proteins implicated in schizophrenia is Neuronal PAS domain protein 3 (NPAS3). NPAS3, a member of the bHLH-PAS superfamily of transcription factors, is involved in the regulation of many processes, such as neurogenesis, metabolism, and circadian rhythms. NPAS3 has been associated with schizophrenia through genetics, including a familial translocation [2], and more recently a V304I mutation, which causes aggregation, was found in a family [3]. We performed a Western Blot analysis of post mortem brain samples obtained from the Human Brain Tissue Bank, Semmelweis University, Budapest. Additionally, we investigated overexpressed NPAS3 vectors in neuroblastoma cells, inducing after oxidative stress, induced by sodium arsenite treatment. Insoluble NPAS3 insolubility was seen in 74 % of brains examined, which is far more than can be explained by the V304I mutation, and suggesting other mechanisms to exist. In cell systems, NPAS3 aggregation did not depend on V304I mutation, with both wild- type and mutant NPAS3 showed cytoplasmic localization after stress inducement. Based on our research, it appears that NPAS3 aggregation in the brain is a more widespread phenomenon than first predicted. We are now investigating its relevance to clinical diagnosis. [1] Bradshaw NJ, Korth C. (2019) Protein misassembly and aggregation as potential convergence points for non- -genetic causes of chronic mental illness. Mol Psychiatry 24: 936–951. [2] Nucifora LG, Wu YC, Lee BJ, Sha L, Margolis RL, Ross CA et al. (2016) A Mutation in NPAS3 That Segregates with Schizophrenia in a Small Family Leads to Protein Aggregation. Mol Neuropsychiatry 2: 133– 144. [3] Kamnasaran D, Muir W, Ferguson-Smith M, Cox D. (2003) Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J Med Genet 40: 325– 332.

NPAS3, schizophrenia, protein aggregation, oxidative stress

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