Pallidin protein in neurodevelopment and its relation to the pathogenesis of schizophrenia

Pallidin is a protein found throughout the nervous system and it has been linked to the development of schizophrenia. At the same time, it has been suggested that schizophrenia is a neurodevelopmental disease. The p38 protein participates in neuronal differentiation and apoptosis. We hypothesized pallidin and p38 play a role in neural system development and the pathogenesis of schizophrenia, and designed several experiments to test this possibility. During pull-down experiments GST-pallidin was able to bind His-Ndn (an HDAC3 binding protein) in vitro. In cells co-transfected with HDAC3 and p38, the transcriptional activity of p38 was significantly inhibited by HDAC3. When pallidin was overexpressed, the transcriptional activity of the endogenous HDAC3 improved significantly. Overexpression of pallidin-EGFP in HCT116 p38 wild-type cells increased the endogenous p21 protein and the mRNA levels. The decrease in the expression of endogenous p38 affected the differentiation of N2a cells. The lengths of the neurites generated in the experimental group were significantly shorter than those in the control group. We conclude that pallidin indirectly regulates the transcriptional activity of p38 during neurodevelopment by binding HDAC3 and changing its cellular localization, which leaves p38 uninhibited. Moreover, since pallidin can also affect neuronal differentiation and its variants seem to be related to an increased risk of schizophrenia, it is possible that both pallidin and p38 play a role in the pathogenesis of the disease.