The PSD Protein ProSAP2/Shank3 Displays Synapto-Nuclear Shuttling Which Is Deregulated in a Schizophrenia-Associated Mutation

Exp Neurol. 2014 Mar;253:126-37. doi: 10.1016/j.expneurol.2013.12.015. Epub 2013 Dec 29.

Abstract

Recently, mutations in ProSAP2/Shank3 have been discovered as one of the genetic factors for schizophrenia (SCZ). Here, we show that the postsynaptic density protein ProSAP2/Shank3 undergoes activity dependent synapse-to-nucleus shuttling in hippocampal neurons. Our study shows that the de novo mutation (R1117X) in ProSAP2/Shank3 that was identified in a patient with SCZ leads to an accumulation of mutated ProSAP2/Shank3 within the nucleus independent of synaptic activity. Furthermore, we identified novel nuclear ProSAP2/Shank3 interaction partners. Nuclear localization of mutated ProSAP2/Shank3 alters transcription of several genes, among them already identified genetic risk factors for SCZ such as Synaptotagmin 1 and LRRTM1. Comparing the SCZ mutation of ProSAP2/Shank3 to the knockdown of ProSAP2/Shank3 we found some shared features such as reduced synaptic density in neuronal cultures. However, hippocampal neurons expressing the ProSAP2/Shank3 SCZ mutation furthermore show altered E/I ratio and reduced dendritic branching. Thus, we conclude that the uncoupling of ProSAP2/Shank3 nuclear shuttling from synaptic activity may represent a molecular mechanism that contributes to the pathology of SCZ in patients with mutations in ProSAP2/Shank3.

Keywords: Autism; LRRTM1; Nuclear shuttling; PSD; SCZ; Shank3; Synapse; Synaptotagmin 1; hnRNP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / genetics
  • COS Cells
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Embryo, Mammalian
  • Gene Expression Regulation / genetics*
  • Hippocampus / cytology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microarray Analysis
  • Mutation / genetics*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Cell Adhesion Molecules / metabolism
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Rats
  • Synapses / metabolism*
  • Time Factors

Substances

  • LRRTM1 protein, mouse
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules
  • SHANK3 protein, human
  • Arginine