Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95

Cell. 2012 Dec 21;151(7):1581-94. doi: 10.1016/j.cell.2012.11.040.

Abstract

The activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) induces excitatory synapse elimination in mouse neurons, which requires fragile X mental retardation protein (FMRP), an RNA-binding protein implicated in human cognitive dysfunction and autism. We report here that protocadherin 10 (Pcdh10), an autism-spectrum disorders gene, is necessary for this process. MEF2 and FMRP cooperatively regulate the expression of Pcdh10. Upon MEF2 activation, PSD-95 is ubiquitinated by the ubiquitin E3 ligase murine double minute 2 (Mdm2) and then binds to Pcdh10, which links it to the proteasome for degradation. Blockade of the Pcdh10-proteasome interaction inhibits MEF2-induced PSD-95 degradation and synapse elimination. In FMRP-lacking neurons, elevated protein levels of eukaryotic translation elongation factor 1 α (EF1α), an Mdm2-interacting protein and FMRP target mRNA, sequester Mdm2 and prevent MEF2-induced PSD-95 ubiquitination and synapse elimination. Together, our findings reveal roles for multiple autism-linked genes in activity-dependent synapse elimination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics
  • Autistic Disorder / metabolism
  • Cadherins / metabolism
  • Dendrites / metabolism
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Guanylate Kinases / metabolism*
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Humans
  • In Vitro Techniques
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Myogenic Regulatory Factors / genetics
  • Myogenic Regulatory Factors / metabolism
  • Neurons / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Synapses / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Cadherins
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Fmr1 protein, mouse
  • Membrane Proteins
  • Myogenic Regulatory Factors
  • Pcdh10 protein, mouse
  • Fragile X Mental Retardation Protein
  • Ubiquitin-Protein Ligases
  • Guanylate Kinases
  • Proteasome Endopeptidase Complex