title: The schizophrenia susceptibility factor dysbindin and its associated complex sort cargoes from cell bodies to the synapse.
abstract: Dysbindin assembles into the biogenesis of lysosome-related organelles complex 1 (BLOC-1), which interacts with the adaptor protein complex 3 (AP-3), mediating a common endosome-trafficking route. Deficiencies in AP-3 and BLOC-1 affect synaptic vesicle composition. However, whether AP-3-BLOC-1-dependent sorting events that control synapse membrane protein content take place in cell bodies upstream of nerve terminals remains unknown. We tested this hypothesis by analyzing the targeting of phosphatidylinositol-4-kinase type II α (PI4KIIα), a membrane protein present in presynaptic and postsynaptic compartments. PI4KIIα copurified with BLOC-1 and AP-3 in neuronal cells. These interactions translated into a decreased PI4KIIα content in the dentate gyrus of dysbindin-null BLOC-1 deficiency and AP-3-null mice. Reduction of PI4KIIα in the dentate reflects a failure to traffic from the cell body. PI4KIIα was targeted to processes in wild-type primary cultured cortical neurons and PC12 cells but failed to reach neurites in cells lacking either AP-3 or BLOC-1. Similarly, disruption of an AP-3-sorting motif in PI4KIIα impaired its sorting into processes of PC12 and primary cultured cortical neuronal cells. Our findings indicate a novel vesicle transport mechanism requiring BLOC-1 and AP-3 complexes for cargo sorting from neuronal cell bodies to neurites and nerve terminals.
authors: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
authors: Jennifer
authors: J
authors: Larimore
authors: Karine
authors: K
authors: Tornieri
authors: Pearl V
authors: PV
authors: Ryder
authors: Avanti
authors: A
authors: Gokhale
authors: Stephanie A
authors: SA
authors: Zlatic
authors: Branch
authors: B
authors: Craige
authors: Joshua D
authors: JD
authors: Lee
authors: Konrad
authors: K
authors: Talbot
authors: Jean-Francois
authors: JF
authors: Pare
authors: Yoland
authors: Y
authors: Smith
authors: Victor
authors: V
authors: Faundez
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism*; D022161:Transport Vesicles / Q000235:genetics / Q000378:metabolism*
chemical_list: D033963:Adaptor Protein Complex 3; C513476:Bloc1s6 protein, mouse; D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D009419:Nerve Tissue Proteins