Related Experiment Video

Updated: May 11, 2026

Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins
09:07

Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins

Published on: August 15, 2017

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

Nien-Pei Tsai1, Julia R Wilkerson, Weirui Guo

  • 1Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Cell
|December 25, 2012
PubMed

Insights

Myocyte enhancer factor 2 (MEF2) and fragile X mental retardation protein (FMRP) control synapse elimination via protocadherin 10 (Pcdh10). This pathway involves PSD-95 degradation and is disrupted in FMRP-deficient neurons, highlighting autism gene roles.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) regulates excitatory synapse elimination in neurons.
  • Fragile X mental retardation protein (FMRP), linked to cognitive dysfunction and autism, is crucial for this process.
  • Autism-spectrum disorders (ASDs) are associated with genetic factors influencing neuronal development and function.

Purpose of the Study:

  • To investigate the role of protocadherin 10 (Pcdh10), an ASD gene, in MEF2- and FMRP-mediated synapse elimination.
  • To elucidate the molecular mechanisms underlying MEF2-induced PSD-95 degradation and its regulation by FMRP.
  • To understand how FMRP deficiency impacts synapse elimination pathways.

Main Methods:

  • Investigated the cooperative regulation of Pcdh10 expression by MEF2 and FMRP.
  • Utilized ubiquitination assays to examine PSD-95 modification by Mdm2.
  • Studied the interaction between Pcdh10 and the proteasome.
  • Analyzed the effect of FMRP deficiency on Mdm2 activity and PSD-95 ubiquitination using EF1α as a mediator.

Main Results:

  • Pcdh10 is essential for MEF2-induced excitatory synapse elimination.
  • MEF2 activation leads to Mdm2-mediated ubiquitination and proteasomal degradation of PSD-95, a process dependent on Pcdh10.
  • In FMRP-deficient neurons, elevated EF1α sequesters Mdm2, inhibiting PSD-95 ubiquitination and synapse elimination.
  • Blockade of the Pcdh10-proteasome interaction prevents MEF2-induced PSD-95 degradation and synapse elimination.

Conclusions:

  • MEF2 and FMRP cooperatively regulate Pcdh10 expression, which is critical for activity-dependent synapse elimination.
  • The findings reveal a novel mechanism involving Pcdh10, Mdm2, and PSD-95 in regulating synaptic plasticity.
  • Dysregulation of this pathway, particularly in the absence of FMRP due to elevated EF1α, contributes to synaptic abnormalities observed in fragile X syndrome and potentially other ASDs.
  • Multiple autism-linked genes play significant roles in activity-dependent synapse elimination processes.

More Related Videos

Evaluation of Synapse Density in Hippocampal Rodent Brain Slices07:44

Evaluation of Synapse Density in Hippocampal Rodent Brain Slices

Published on: October 6, 2017

Dynamic Clamp Methods to Investigate Impaired Neuronal Excitability Associated with Autism08:44

Dynamic Clamp Methods to Investigate Impaired Neuronal Excitability Associated with Autism

Published on: October 17, 2025

Related Concept Videos

The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
Lysosomal Hydrolases01:22

Lysosomal Hydrolases

Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
The Proteasome01:13

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
Psychosis: Pathophysiology of Schizophrenia and Other Psychotic Disorders01:27

Psychosis: Pathophysiology of Schizophrenia and Other Psychotic Disorders

Schizophrenia is a neurodevelopmental disorder whose origins are rooted in complex genetic components. Despite our burgeoning understanding, the pathophysiology of this disorder remains incompletely deciphered.
Researchers have identified genetic factors that increase susceptibility to schizophrenia, underscoring the intricate interplay between genetics and environment in disease development. At the core of schizophrenia's pathophysiology is excessive dopaminergic neurotransmission within the...
Parkinson Disease ll: Pathophysiology01:24

Parkinson Disease ll: Pathophysiology

Parkinson disease (PD) is a progressive neurodegenerative disorder primarily affecting movement, with additional non-motor features. Its pathophysiology involves complex interactions among genetic susceptibility, environmental exposures, and cellular dysfunction, including dopaminergic neuron loss, protein aggregation, and mitochondrial impairment.Selective NeurodegenerationA key feature is the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to reduced...