Abstract
Recent molecular genetic studies have identified 100s of risk genes for various neurodevelopmental and neuropsychiatric disorders. As the number of risk genes increases, it is becoming clear that different mutations of a single gene could cause different types of disorders. One of the best examples of such a gene is SHANK3, which encodes a core scaffold protein of the neuronal excitatory post-synapse. Deletions, duplications, and point mutations of SHANK3 are associated with autism spectrum disorders, intellectual disability, schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Nevertheless, how the different mutations of SHANK3 can lead to such phenotypic diversity remains largely unknown. In this study, we investigated whether Shank3 could form protein complexes in a brain region-specific manner, which might contribute to the heterogeneity of neuronal pathophysiology caused by SHANK3 mutations. To test this, we generated a medial prefrontal cortex (mPFC) Shank3 in vivo interactome consisting of 211 proteins, and compared this protein list with a Shank3 interactome previously generated from mixed hippocampal and striatal (HP+STR) tissues. Unexpectedly, we found that only 47 proteins (about 20%) were common between the two interactomes, while 164 and 208 proteins were specifically identified in the mPFC and HP+STR interactomes, respectively. Each of the mPFC- and HP+STR-specific Shank3 interactomes represents a highly interconnected network. Upon comparing the brain region-enriched proteomes, we found that the large difference between the mPFC and HP+STR Shank3 interactomes could not be explained by differential protein expression profiles among the brain regions. Importantly, bioinformatic pathway analysis revealed that the representative biological functions of the mPFC- and HP+STR-specific Shank3 interactomes were different, suggesting that these interactors could mediate the brain region-specific functions of Shank3. Meanwhile, the same analysis on the common Shank3 interactors, including Homer and GKAP/SAPAP proteins, suggested that they could mainly function as scaffolding proteins at the post-synaptic density. Lastly, we found that the mPFC- and HP+STR-specific Shank3 interactomes contained a significant number of proteins associated with neurodevelopmental and neuropsychiatric disorders. These results suggest that Shank3 can form protein complexes in a brain region-specific manner, which might contribute to the pathophysiological and phenotypic diversity of disorders related to SHANK3 mutations.
Highlights
Recent genome-wide molecular genetic studies on human patients have identified 100s of risk genes for neurodevelopmental and neuropsychiatric disorders including autism spectrum disorders (ASDs), intellectual disability, schizophrenia (SCZ), bipolar disorder (BD), and depression
We propose a hypothesis that the brain region-specific Shank3 interactomes might contribute to the heterogeneity of neuronal pathophysiology and the diversity of phenotypes related to SHANK3 mutations
We generated a Shank3 in vivo interactome by performing IP followed by mass spectrometry analysis of the mixed HP and STR (HP+STR) synaptosomal P2 DOC lysates from 5-week-old EGFP-Shank3 TG mice (Han et al, 2013)
Summary
Recent genome-wide molecular genetic studies on human patients have identified 100s of risk genes for neurodevelopmental and neuropsychiatric disorders including autism spectrum disorders (ASDs), intellectual disability, schizophrenia (SCZ), bipolar disorder (BD), and depression. Variety of point mutations and small deletions in the SHANK3 gene have been found in patients with ASDs, intellectual disability, and SCZ (Durand et al, 2007; Gauthier et al, 2010; Grabrucker et al, 2011; Jiang and Ehlers, 2013; Guilmatre et al, 2014; Leblond et al, 2014). Many of the risk genes for neurodevelopmental and neuropsychiatric disorders are involved in regulating synaptic development and function (van Spronsen and Hoogenraad, 2010; Zoghbi and Bear, 2012; Hall et al, 2015). As Shank is an abundant core synaptic protein, studying SHANK3 gene as a leading case can provide some insight into the mechanisms by which different variants of a single gene, especially one functioning at the synapse, can lead to phenotypic diversity
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