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

Nien Pei Tsai, Julia R. Wilkerson, Weirui Guo, Marina A. Maksimova, George N. Demartino, Christopher W. Cowan, Kimberly M. Huber

Research output: Contribution to journalArticle

170 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1581-1594
Number of pages14
JournalCell
Volume151
Issue number7
DOIs
StatePublished - Dec 21 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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