Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

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

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

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

BioGRID (Data, Interactions)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.