Emerging Roles of ARHGAP33 in Intracellular Trafficking of TrkB and Pathophysiology of Neuropsychiatric Disorders

Nat Commun. 2016 Feb 3;7:10594. doi: 10.1038/ncomms10594.

Abstract

Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Adult
  • Animals
  • Behavior, Animal*
  • Brain / metabolism
  • Brain / pathology
  • Case-Control Studies
  • Cells, Cultured
  • Dendritic Spines / genetics*
  • Dendritic Spines / metabolism
  • Female
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • In Situ Hybridization
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Neurons / metabolism*
  • Patch-Clamp Techniques
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Protein Transport / genetics*
  • RNA, Messenger / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptor, trkB / metabolism*
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Schizophrenia / pathology
  • Sorting Nexins / genetics*
  • Sorting Nexins / metabolism
  • Synapses / genetics*
  • Synapses / metabolism

Substances

  • ARHGAP33 protein, human
  • Adaptor Proteins, Vesicular Transport
  • GTPase-Activating Proteins
  • RNA, Messenger
  • SNX26 protein, mouse
  • Sorting Nexins
  • Receptor, trkB
  • sortilin