Multiple Autism-Linked Genes Mediate Synapse Elimination via Proteasomal Degradation of a Synaptic Scaffold PSD-95

• Published in: Cell 2012-12, Vol.151 (7), p.1581-1594
• Main Authors: Tsai, Nien-Pei, Wilkerson, Julia R., Guo, Weirui, Maksimova, Marina A., DeMartino, George N., Cowan, Christopher W., Huber, Kimberly M.
• Format: Article
• Language: English
• Subjects: Animals; Autism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Cadherins - metabolism; cognition; degradation; 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; genes; Guanylate Kinases - metabolism; Hippocampus - cytology; Hippocampus - metabolism; Humans; In Vitro Techniques; Membrane Proteins - metabolism; messenger RNA; Mice; Mice, Inbred C57BL; Myogenic Regulatory Factors - genetics; Myogenic Regulatory Factors - metabolism; neurons; Neurons - metabolism; proteasome endopeptidase complex; Proteasome Endopeptidase Complex - metabolism; RNA-binding proteins; synapse; Synapses - metabolism; transcription factors; translation (genetics); ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.11.040

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. [Display omitted] ► 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 The activity-dependent transcription factor MEF2 is found to induce synapse elimination through the ubiquitination and degradation of the postsynaptic scaffolding protein PSD-95. Further, the autism-linked genes protocadherin 10 and fragile X mental retardation 1 are shown to have distinct roles in PSD-95 proteosomal degradation and synapse elimination.