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Interactions of human truncated DISC1 proteins: implications for schizophrenia.

ABSTRACT: Numerous genetic linkage and association reports have implicated the Disrupted-in-Schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-associated alleles. Investigation into the protein-protein interactions of alternative DISC1 isoforms may provide information about the functional consequences of overexpression of truncated forms in mental illness. Human embryonic kidney (HEK293) cells were transiently co-transfected with human epitope-tagged DISC1 variants and epitope-tagged NDEL1, FEZ1, GSK3? and PDE4B constructs. Co-immunoprecipitation assays demonstrated that all truncated DISC1 variants formed complexes with full-length DISC1. Short DISC1 splice variants L?78, L?3 and Esv1 showed reduced or no binding to NDEL1 and PDE4B proteins, but fully interacted with FEZ1 and GSK3?. The temporal expression pattern of GSK3? in the human postmortem tissue across the lifespan closely resembled that of the truncated DISC1 variants, suggesting the possibility of interactions between these proteins in the human brain. Our results suggest that complexes of full-length DISC1 with truncated DISC1 variants may result in cellular disturbances critical to DISC1 function.

SUBMITTER: Newburn EN

PROVIDER: S-EPMC3309510 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Interactions of human truncated DISC1 proteins: implications for schizophrenia.

Newburn E N EN Hyde T M TM Ye T T Morita Y Y Weinberger D R DR Kleinman J E JE Lipska B K BK

Translational psychiatry 20110816

Numerous genetic linkage and association reports have implicated the Disrupted-in-Schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-as ...[more]

PMID: 22832604

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Project description:Both Disrupted-In-Schizophrenia-1 (DISC1) and dopamine receptors D2R have significant contributions to the pathogenesis of schizophrenia. Our previous study demonstrated that DISC1 binds to D2R and such protein-protein interaction is enhanced in patients with schizophrenia and Disc1-L100P mouse model of schizophrenia (Su et al., 2014). By uncoupling DISC1 × D2R interaction (trans-activator of transcription (TAT)-D2pep), the synthesized TAT-peptide elicited antipsychotic-like effects in pharmacological and genetic animal models, without motor side effects as tardive dyskinesia commonly seen with typical antipsychotic drugs (APDs), indicating that the potential of TAT-D2pep of becoming a new APD. Therefore, in the current study, we further explored the APD-associated capacities of TAT-D2pep. We found that TAT-D2pep corrected the disrupted latent inhibition (LI), as a hallmark of schizophrenia associated endophenotype, in Disc1-L100P mutant mice-a genetic model of schizophrenia, supporting further APD' capacity of TAT-D2pep. Moreover, we found that TAT-D2pep elicited nootropic effects in C57BL/6NCrl inbred mice, suggesting that TAT-D2pep acts as a cognitive enhancer, a desirable feature of APDs of the new generation. Namely, TAT-D2pep improved working memory in T-maze, and cognitive flexibility assessed by the LI paradigm, in C57BL/6N mice. Next, we assessed the impact of TAT-D2pep on hippocampal long-term plasticity (LTP) under basal conditions and upon stimulation of D2 receptors using quinpirole. We found comparable effects of TAT-D2pep and its control TAT-D2pep-scrambled peptide (TAT-D2pep-sc) under basal conditions. However, under stimulation of D2R by quinpirole, LTP was enhanced in hippocampal slices incubated with TAT-D2pep, supporting the notion that TAT-D2pep acts in a dopamine-dependent manner and acts as synaptic enhancer. Overall, our experiments demonstrated implication of DISC1 × D2R protein-protein interactions into mechanisms of cognitive and synaptic plasticity, which help to further understand molecular-cellular mechanisms of APD of the next generation.

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Interactions of human truncated DISC1 proteins: implications for schizophrenia.

Publications

Interactions of human truncated DISC1 proteins: implications for schizophrenia.

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