Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders.

Full Abstract

Disrupted In Schizophrenia 1 (DISC1) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have demonstrated that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel. The complex is abundant at E17 and in early postnatal life but is greatly reduced in the adult. Nudel has previously been shown to bind Lis1, a gene underlying lissencephaly in humans. Critically, we show that the predicted peptide product resulting from the Scottish translocation removes the interaction domain for Nudel. DISC1 interacts with Nudel through a leucine zipper domain and binds to a novel DISC1-interaction domain on Nudel, which is independent from the Lis1 binding site. We show that Nudel is able to act as a bridge between DISC1 and Lis1 to allow formation of a trimolecular complex. Nudel has been implicated to play a role in neuronal migration, together with the developmental variation in the abundance of the DISC1-Nudel complex, may implicate a defective DISC1-Nudel complex as a neurodevelopmental cause of schizophrenia.

Author information

Author/s: Brandon, N J (NJ); Handford, E J (EJ); Schurov, I (I); Rain, J-C (JC); Pelling, M (M); Duran-Jimeniz, B (B); Camargo, L M (LM); Oliver, K R (KR); Beher, D (D); Shearman, M S (MS); Whiting, P J (PJ);

Affiliation: Merck Sharp and Dohme, The Neuroscience Research Centre, Harlow, Essex, CM20 2QR, UK. nick_brandon(-atsign-)merck.com

Journal and publication information

Publication Type: Journal Article

Journal: Molecular and cellular neurosciences (Mol Cell Neurosci), published in United States. (Language: eng)

Reference: 2004-Jan; vol 25 (issue 1) : pp 42-55

Dates: Created 2004/02/13; Completed 2004/05/19; Revised 2006/11/15;

PMID: 14962739, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

1-Alkyl-2-acetylglycerophosphocholine Esterase
Amino Acid Sequence - genetics
Animals
Binding Sites - genetics
Brain - abnormalities; pathology; physiopathology
Cell Movement - genetics
Gene Expression Regulation, Developmental - genetics
Humans
Leucine Zippers - genetics
Macromolecular Substances
Mice

Mice
Microtubule-Associated Proteins - metabolism
Microtubules - metabolism
Mutation - genetics
Nerve Tissue Proteins - genetics; metabolism
Protein Binding - genetics
Protein Structure, Tertiary - genetics
Schizophrenia - genetics; metabolism; physiopathology
Serine Endopeptidases - genetics; metabolism
Translocation, Genetic - genetics
Tumor Cells, Cultured

Associated Chemicals: DISC1 protein, human (0) ; Disc1 protein, mouse (0) ; Macromolecular Substances (0) ; Microtubule-Associated Proteins (0) ; Nerve Tissue Proteins (0) ; 1-Alkyl-2-acetylglycerophosphocholine Esterase (EC 3.1.1.47) ; PAFAH1B1 protein, human (EC 3.1.1.47) ; Pafah1b1 protein, mouse (EC 3.1.1.47) ; Serine Endopeptidases (EC 3.4.21.-)

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