Cell
Volume 151, Issue 7, 21 December 2012, Pages 1581-1594
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Article
Multiple Autism-Linked Genes Mediate Synapse Elimination via Proteasomal Degradation of a Synaptic Scaffold PSD-95

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Summary

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.

Highlights

► The transcription factor MEF2 induces Pcdh10 that is required for synapse elimination ► MEF2 stimulates ubiquitination of PSD-95 by the ubiquitin E3 ligase Mdm2 ► Pcdh10 chaperones ubiquitinated PSD-95 to proteasome ► Elevated EF1α in Fmr1 KO neuron blocks Mdm2 and MEF2-mediated synapse elimination

Cited by (0)

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These authors contributed equally to this work

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Present address: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA