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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 ? (PI4KII?), a membrane protein present in presynaptic and postsynaptic compartments. PI4KII? copurified with BLOC-1 and AP-3 in neuronal cells. These interactions translated into a decreased PI4KII? content in the dentate gyrus of dysbindin-null BLOC-1 deficiency and AP-3-null mice. Reduction of PI4KII? in the dentate reflects a failure to traffic from the cell body. PI4KII? 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 PI4KII? 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.

SUBMITTER: Larimore J 

PROVIDER: S-EPMC3237628 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

Larimore Jennifer J   Tornieri Karine K   Ryder Pearl V PV   Gokhale Avanti A   Zlatic Stephanie A SA   Craige Branch B   Lee Joshua D JD   Talbot Konrad K   Pare Jean-Francois JF   Smith Yoland Y   Faundez Victor V  

Molecular biology of the cell 20111012 24


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 phospha  ...[more]

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