title: DISC1, PDE4B, and NDE1 at the centrosome and synapse.
abstract: Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.
authors.affiliation: Medical Genetics Section, Molecular Medicine Centre, Crewe Road, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bradshaw
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ogawa
authors.forename: Beatriz
authors.initials: B
authors.lastname: Antolin-Fontes
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Chubb
authors.forename: Becky C
authors.initials: BC
authors.lastname: Carlyle
authors.forename: Sheila
authors.initials: S
authors.lastname: Christie
authors.forename: Antoine
authors.initials: A
authors.lastname: Claessens
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: J Kirsty
authors.initials: JK
authors.lastname: Millar
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000378:metabolism; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D013569:Synapses / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; C412476:DISC1 protein, human; D008869:Microtubule-Associated Proteins; C525094:Nde1 protein, human; D009419:Nerve Tissue Proteins; D051701:Activating Transcription Factor 4; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human