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

Mol Biol Cell. 2011 Dec;22(24):4854-67. doi: 10.1091/mbc.E11-07-0592. Epub 2011 Oct 12.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Protein Complex 3 / genetics
  • Adaptor Protein Complex 3 / metabolism*
  • Amino Acid Motifs
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lectins / genetics
  • Lectins / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurites / metabolism*
  • PC12 Cells
  • Rats
  • Synaptic Membranes / genetics
  • Synaptic Membranes / metabolism*
  • Transport Vesicles / genetics
  • Transport Vesicles / metabolism*

Substances

  • Adaptor Protein Complex 3
  • Bloc1s6 protein, mouse
  • Carrier Proteins
  • Dtnbp1 protein, mouse
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lectins
  • Nerve Tissue Proteins