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

Cell | Dec 21, 2012

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.

Pubmed ID: 23260144 RIS Download

Mesh terms: Animals | Autistic Disorder | Cadherins | Dendrites | Disease Models, Animal | Fragile X Mental Retardation Protein | Fragile X Syndrome | Guanylate Kinases | Hippocampus | Humans | In Vitro Techniques | Membrane Proteins | Mice | Mice, Inbred C57BL | Myogenic Regulatory Factors | Neurons | Proteasome Endopeptidase Complex | Synapses | Ubiquitin-Protein Ligases | Ubiquitination

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Associated grants

  • Agency: NICHD NIH HHS, Id: F32HD062120
  • Agency: NICHD NIH HHS, Id: R01 HD052731
  • Agency: NINDS NIH HHS, Id: NS045711,
  • Agency: NINDS NIH HHS, Id: R01 NS045711
  • Agency: NICHD NIH HHS, Id: F32HD069111
  • Agency: NICHD NIH HHS, Id: F32 HD062120
  • Agency: NICHD NIH HHS, Id: HD052731
  • Agency: NICHD NIH HHS, Id: F32 HD069111
  • Agency: NIDA NIH HHS, Id: R01 DA027664

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