title: Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95.
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.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nien-Pei
authors.initials: NP
authors.lastname: Tsai
authors.forename: Julia R
authors.initials: JR
authors.lastname: Wilkerson
authors.forename: Weirui
authors.initials: W
authors.lastname: Guo
authors.forename: Marina A
authors.initials: MA
authors.lastname: Maksimova
authors.forename: George N
authors.initials: GN
authors.lastname: DeMartino
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cowan
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000091363:Protocadherins; D013569:Synapses / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D015820:Cadherins; D000076122:Disks Large Homolog 4 Protein; D051860:Fragile X Messenger Ribonucleoprotein 1; D051528:Guanylate Kinases; D008565:Membrane Proteins; D018006:Myogenic Regulatory Factors; D046988:Proteasome Endopeptidase Complex; D000091363:Protocadherins; D044767:Ubiquitin-Protein Ligases; C501447:Dlg4 protein, mouse; C497684:Fmr1 protein, mouse; C117277:Pcdh10 protein, mouse