Differential protein expression of DARPP-32 versus Calcineurin in the prefrontal cortex and nucleus accumbens in schizophrenia and bipolar disorder

Abstract

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) integrates dopaminergic signaling into that of several other neurotransmitters. Calcineurin (CaN), located downstream of dopaminergic pathways, inactivates DARPP-32 by dephosphorylation. Despite several studies have examined their expression levels of gene and protein in postmortem patients’ brains, they rendered inconsistent results. In this study, protein expression levels of DARPP-32 and CaN were measured by enzyme-linked immunosorbent assay (ELISA) in the prefrontal cortex (PFC), and nucleus accumbens (NAc) of 49 postmortem samples from subjects with schizophrenia, bipolar disorder, and normal controls. We also examined the association between this expression and genetic variants of 8 dopaminergic system-associated molecules for 55 SNPs in the same postmortem samples. In the PFC of patients with schizophrenia, levels of DARPP-32 were significantly decreased, while those of CaN tended to increase. In the NAc, both of DARPP-32 and CaN showed no significant alternations in patients with schizophrenia or bipolar disorder. Further analysis of the correlation of DARPP-32 and CaN expressions, we found that positive correlations in controls and schizophrenia in PFC, and schizophrenia in NAc. In PFC, the expression ratio of DARPP-32/CaN were significantly lower in schizophrenia than controls. We also found that several of the aforementioned SNPs may predict protein expression, one of which was confirmed in a second independent sample set. This differential expression of DARPP-32 and CaN may reflect potential molecular mechanisms underlying the pathogenesis of schizophrenia and bipolar disorder, or differences between these two major psychiatric diseases.

A Homozygous Missense Variant in PPP1R1B/DARPP‐32 Is Associated With Generalized Complex Dystonia

“…39 The majority of PPP1R1B expression data reported in the literature has been generated in animals or brain lysates, or studies have used antibodies that cannot distinguish between the two PPP1R1B isoforms. 37,40,41 Here, we characterized the expression of the full length PPP1R1B in human brain using an antibody targeting the N terminal domain of the protein (amino acids 2-34). Although we cannot exclude that the distribution may differ in patient brains, PPP1R1B in control brain was mainly expressed in striatal projection neurons (SPN) localized in the in the caudate (C)putamen (P) and striosomes.…”

Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes

“…However, fine-mapping of the corresponding genomic locus prioritized PPP3R1 with a posterior probability of 0.63 in the 90%-credible gene set. PPP3R1 encodes for calcineurin subunit B type 1 protein, which functions downstream of dopaminergic pathways 11 . Calcineurin contains iron and zinc in its active site and is regulated by oxidation of an iron cofactor 12 , 13 .…”

“…Although the role of altered dopaminergic function and brain-iron homoeostasis in RLS has been well characterized 14 , 15 , none of the previously identified candidate genes were directly implicated as key molecules in dopaminergic neuro-transmission 15 . Being implicated in iron homeostasis 16 , as well as expressed mostly in dopamine receptor-positive neurons 11 , suggests PPP3R1 as a candidate gene for the altered brain iron homeostasis and disrupted dopaminergic function leading to the manifestation of RLS.…”

A Proteomics Analysis of Calmodulin-Binding Proteins in Dictyostelium discoideum during the Transition from Unicellular Growth to Multicellular Development

“…CTSD, together with calcineurin, have been shown to protect against alpha-synuclein toxicity in a yeast model of Parkinson’s disease [ 53 ]. Calcineurin has also been linked to autoimmune diseases (e.g., rheumatoid arthritis), psychiatric diseases (e.g., schizophrenia, bipolar disorder), and hypertension [ 54 , 55 , 56 ]. Importantly, the Dictyostelium homolog of human calcineuin, CanA, was identified by mass spectrometry in starved cells.…”