Analysis of mRNA and Protein Levels of CAP2, DLG1 and ADAM10 Genes in Post-Mortem Brain of Schizophrenia, Parkinson's and Alzheimer's Disease Patients.

Anna Di Maio,Alessandro Usiello,Monica Di Luca,Benedetta Marciano,Silvia Pelucchi,Elena Marcello,Andrea M Isidori,Andrea De Bartolomeis,Arianna De Rosa,Fabrizio Gardoni,Francesco Errico,Tommaso Nuzzo,Martina Garofalo

doi:10.3390/ijms23031539

Abstract

Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin-binding protein cyclase-associated protein 2 (CAP2), the sheddase a disintegrin and metalloproteinase 10 (ADAM10), and the synapse-associated protein 97 (SAP97). Our analysis of the SCZ post-mortem brain indicated increased DLG1 mRNA in DLPFC and decreased CAP2 mRNA in the hippocampus of SCZ patients, compared to non-psychiatric control subjects, while the ADAM10 transcript was unaffected. Conversely, no differences in CAP2, SAP97, and ADAM10 protein levels were detected between SCZ and control individuals in both brain regions. To assess whether DLG1 and CAP2 transcript alterations were selective for SCZ, we also measured their expression in the superior frontal gyrus of patients affected by neurodegenerative disorders, like Parkinson’s and Alzheimer’s disease. Interestingly, also in Parkinson’s disease patients, we found a selective reduction of CAP2 mRNA levels relative to controls but unaltered protein levels. Taken together, we reported for the first time altered CAP2 expression in the brain of patients with psychiatric and neurological disorders, thus suggesting that aberrant expression of this gene may contribute to synaptic dysfunction in these neuropathologies.

Highlights

Schizophrenia (SCZ) is a polygenic and multifactorial disorder with complex phenotypes encompassing multiple domains, such as delusions and hallucinations, avolition, anhedonia, lack of social interaction, and deficit of executive functions [1,2]
Consistent with the main role of such pathways in regulating dendritic spine morphology and functions, here we investigated within dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ brains, the expression levels of three synaptic elements that can be regarded as key spine shapers: the actin-binding protein cyclase-associated protein 2 (CAP2) [23], the sheddase a disintegrin and metalloproteinase 10, and its binding partner the synapse-associated protein 97 (SAP97) [24], responsible for the trafficking of ADAM10 and glutamate receptor subunits to the synaptic membrane [25]
The actin-binding proteins CAP2, ADAM10, and its binding partner synapseassociated protein 97 (SAP97) are synaptic proteins enriched in the postsynaptic compartment (Figure 1a) and their synaptic localization is finely modulated by activity-dependent synaptic plasticity [23,26]

Summary

Introduction

Schizophrenia (SCZ) is a polygenic and multifactorial disorder with complex phenotypes encompassing multiple domains, such as delusions and hallucinations (positive symptoms), avolition, anhedonia, lack of social interaction (negative symptoms), and deficit of executive functions (cognitive symptoms) [1,2]. SCZ has been conceptualized as a neurodevelopmental disorder [3,4] affecting synaptic plasticity [4] and cortical–subcortical connectome. Dendritic spines are critical elements of brain circuits since they establish most excitatory synapses. The tip of dendritic spines contains a disk-shaped structure, named the postsynaptic density (PSD), that is believed to be deranged in SCZ [5,6]. The PSD is constituted of approximately 1500 molecules including glutamate receptors, scaffolding proteins, adhesion molecules, and enzymes. The PSD has been recognized as a structural and functional hub [7], responsible for postsynaptic signaling and synaptic plasticity. Dendritic spines are highly dynamic elements and have the capacity to undergo structural changes that are tightly coordinated with synaptic function and modifications in glutamate receptors [9]

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Results

Conclusion