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The schizophrenia susceptibility factor dysbindin and its associated complex sort cargoes from cell bodies to the synapse.

Authors: Larimore, J  Tornieri, K  Ryder, PV  Gokhale, A  Zlatic, SA  Craige, B  Lee, JD  Talbot, K  Pare, JF  Smith, Y  Faundez, V 
Citation: Larimore J, etal., Mol Biol Cell. 2011 Dec;22(24):4854-67. doi: 10.1091/mbc.E11-07-0592. Epub 2011 Oct 12.
Pubmed: (View Article at PubMed) PMID:21998198
DOI: Full-text: DOI:10.1091/mbc.E11-07-0592

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 alpha (PI4KIIalpha), a membrane protein present in presynaptic and postsynaptic compartments. PI4KIIalpha copurified with BLOC-1 and AP-3 in neuronal cells. These interactions translated into a decreased PI4KIIalpha content in the dentate gyrus of dysbindin-null BLOC-1 deficiency and AP-3-null mice. Reduction of PI4KIIalpha in the dentate reflects a failure to traffic from the cell body. PI4KIIalpha 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 PI4KIIalpha 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.

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CRRD Object Information
CRRD ID: 8554550
Created: 2014-05-08
Species: All species
Last Modified: 2014-05-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.