Molecular Characterization of Disrupted in Schizophrenia-1 Risk Variant S704C Reveals the Formation of Altered Oligomeric Assembly

Narayanan, Saravanakumar; Arthanari, Haribabu; Wolfe, Michael S.; Wagner, Gerhard

doi:10.1074/jbc.m111.271593

Cited by 27 publications

(43 citation statements)

References 35 publications

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“…Of particular interest in this respect, a C-terminal DISC1 (640-854) fragment expressed in Escherichia coli was shown to interact with NDEL1 when the fragment was in an octameric form in a cell free assay (Leliveld et al, 2008), a finding that was later corroborated with full-length DISC1 (Narayanan et al, 2011). These findings suggest that the multimerization state of DISC1 may critically influence its protein interactions (Brandon et al, 2009).…”

Section: Does Disc1 Fit With These Criteria For a Classical Scaffold supporting

confidence: 51%

“…NDEL1 has been shown to interact with octameric, and depending on the assay used potentially dimeric, forms of DISC1, but not with higher-order oligomers (Leliveld et al, 2008;Narayanan et al, 2011), indicating that the interactions exhibit conformational specificity along with domain specificity. This also raises the obvious possibility of oligomer-specific interactions making DISC1 a multi-potent scaffold protein.…”

Section: Discussionmentioning

confidence: 99%

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Revisiting Disrupted-in-Schizophrenia 1 as a scaffold protein

Yerabham

Weiergräber

Bradshaw

et al. 2013

Biological Chemistry

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Disrupted-in-Schizophrenia 1 (DISC1) is a widely-accepted genetic risk factor for schizophrenia and many other major mental illnesses. Traditionally DISC1 has been referred to as a 'scaffold protein' because of its ability to bind to a wide array of other proteins, including those of importance for neurodevelopment. Here, we review the characteristic properties shared between established scaffold proteins and DISC1. We find DISC1 to have many, but not all, of the characteristics of a scaffold protein, as it affects a considerable number of different, but related, signaling pathways, in most cases through inhibition of key enzymes. Using threading algorithms, the C-terminal portion of DISC1 could be mapped to extended helical structures, yet it may not closely resemble any of the known tertiary folds. While not completely fitting the classification of a classical scaffold protein, DISC1 does appear to be a tightly regulated and multi-faceted inhibitor of a wide range of enzymes from interrelated signaling cascades (Diverse Inhibitor of Signaling Cascades), which together contribute to neurodevelopment and synaptic homeostasis. Consequently, disruption of this complex regulation would be expected to lead to the range of major mental illnesses in which the DISC1 gene has been implicated.

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Section: Does Disc1 Fit With These Criteria For a Classical Scaffold supporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Revisiting Disrupted-in-Schizophrenia 1 as a scaffold protein

Yerabham

Weiergräber

Bradshaw

et al. 2013

Biological Chemistry

View full text Add to dashboard Cite

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“…We chose to include common variants C704 and F607 as they are frequent in the normal population 43 and have been demonstrated to increase the risk to mental illness 4 and, in biophysical studies, DISC1 misassembly. 6, 7 The PrP promoter was utilized for two reasons: first, it provides pan-cellular expression in the brain that has previously been demonstrated for DISC1 44 and, second, it leads to sufficient expression levels for inducing misassembly as successfully demonstrated in non-prion animal models of protein conformational disease. 45, 46 The PrP promoter is broadly active at embryonic day E13.5 in the mouse brain 47 and continues to be expressed into adulthood, while the Disc1 gene has two expression peaks at E13.5 and around postnatal day P35.…”

Section: Resultsmentioning

confidence: 99%

“…6, 7 Both polymorphisms are common alleles that do not predict mental illness as opposed to mutations. Therefore, when evaluating the potential contribution of these polymorphisms on the observed phenotypes, genetic and protein aggregation effects cannot be separated because both phenomena are linked.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the coding polymorphisms S704C (rs821616) and L607F (rs6675281) in DISC1 were associated with mental illness and also showed increased DISC1 protein aggregation in vitro . 6, 7 In parallel, various transgenic or genetically altered mouse models have been developed, either targeting the mouse Disc1 locus or introducing mutant human DISC1 variants. Missense mutations, 8 deletion variants 9, 10 or partial knockout of the endogenous mouse Disc1 locus 11 were generated.…”

Section: Introductionmentioning

confidence: 99%

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Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits

et al. 2016

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Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.

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NDE1 and NDEL1 from genes to (mal)functions: parallel but distinct roles impacting on neurodevelopmental disorders and psychiatric illness

Bradshaw

Hayashi

2016

Cell. Mol. Life Sci.

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NDE1 (Nuclear Distribution Element 1, also known as NudE) and NDEL1 (NDE-Like 1, also known as NudEL) are the mammalian homologues of the fungus nudE gene, with important and at least partially overlapping roles for brain development. While a large number of studies describe the various properties and functions of these proteins, many do not directly compare the similarities and differences between NDE1 and NDEL1. Although sharing a high degree structural similarity and multiple common cellular roles, each protein presents several distinct features that justify their parallel but also unique functions. Notably both proteins have key binding partners in dynein, LIS1 and DISC1, which impact on neurodevelopmental and psychiatric illnesses. Both are implicated in schizophrenia through genetic and functional evidence, with NDE1 also strongly implicated in microcephaly, as well as other neurodevelopmental and psychiatric conditions through copy number variation, while NDEL1 possesses an oligopeptidase activity with a unique potential as a biomarker in schizophrenia. In this review, we aim to give a comprehensive overview of the various cellular roles of these proteins in a "bottom-up" manner, from their biochemistry and protein-protein interactions on the molecular level, up to the consequences for neuronal differentiation, and ultimately to their importance for correct cortical development, with direct consequences for the pathophysiology of neurodevelopmental and mental illness.

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Molecular Characterization of Disrupted in Schizophrenia-1 Risk Variant S704C Reveals the Formation of Altered Oligomeric Assembly

Cited by 27 publications

References 35 publications

Revisiting Disrupted-in-Schizophrenia 1 as a scaffold protein

Revisiting Disrupted-in-Schizophrenia 1 as a scaffold protein

Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits

NDE1 and NDEL1 from genes to (mal)functions: parallel but distinct roles impacting on neurodevelopmental disorders and psychiatric illness

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