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PMID: 23260144 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell ·Vol. 151 ·No. 7 ·2012-12-21 ·Pages 1581-94

Tsai NP, Wilkerson JR, Guo W, Maksimova MA, DeMartino GN, Cowan CW, Huber KM

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.

MeSH Terms
Animals Autistic Disorder/genetics,metabolism Cadherins/metabolism Dendrites/metabolism Disease Models, Animal Disks Large Homolog 4 Protein Fragile X Mental Retardation Protein/genetics,metabolism Fragile X Syndrome/genetics,metabolism Guanylate Kinases/metabolism Hippocampus/cytology,metabolism Humans In Vitro Techniques Membrane Proteins/metabolism Mice Mice, Inbred C57BL Myogenic Regulatory Factors/genetics,metabolism Neurons/metabolism Proteasome Endopeptidase Complex/metabolism Protocadherins Synapses/metabolism Ubiquitin-Protein Ligases/metabolism Ubiquitination
Chemicals
Cadherins Disks Large Homolog 4 Protein Dlg4 protein, mouse Fmr1 protein, mouse Membrane Proteins Myogenic Regulatory Factors Pcdh10 protein, mouse Protocadherins Fragile X Mental Retardation Protein Ubiquitin-Protein Ligases Guanylate Kinases Proteasome Endopeptidase Complex
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Tsai Nien-Pei
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Wilkerson Julia R
Guo Weirui
Maksimova Marina A
DeMartino George N
Cowan Christopher W
Huber Kimberly M
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.11.040
Published
2012-12-21
Pages
1581-94
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3530171
Subset
IM
Grants
NICHD NIH HHS · F32HD062120 · United States
NICHD NIH HHS · R01 HD052731 · United States
NINDS NIH HHS · NS045711, · United States
NINDS NIH HHS · R01 NS045711 · United States
NICHD NIH HHS · HD052731 · United States
NICHD NIH HHS · F32 HD069111 · United States
NIDA NIH HHS · R01 DA027664 · United States
NICHD NIH HHS · F32HD069111 · United States
NICHD NIH HHS · F32 HD062120 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2012.11.040 PMC Full Text View journal details
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