Source 1primary paper2025MED
Toolkit/PFE3
PFE3
Taxonomy: Mechanism Branch / Architecture. Workflows sit above the mechanism and technique branches rather than replacing them.
Summary
First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses.
Usefulness & Problems
Why this is useful
PFE3 is a constitutive genetically encoded excitatory synapse ablator. It directs E3 ligase-dependent degradation machinery to PSD-95 to functionally ablate excitatory synapses.; constitutive ablation of excitatory synapses; manipulating the structure of neural circuits
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PFE3 is a constitutive genetically encoded excitatory synapse ablator. It directs E3 ligase-dependent degradation machinery to PSD-95 to functionally ablate excitatory synapses.
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constitutive ablation of excitatory synapses
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manipulating the structure of neural circuits
Problem solved
It addresses the lack of tools analogous to optogenetic and chemogenetic actuators for manipulating neural circuit structure rather than only activity.; provides a genetically encoded tool for structural manipulation of excitatory synapses
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It addresses the lack of tools analogous to optogenetic and chemogenetic actuators for manipulating neural circuit structure rather than only activity.
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provides a genetically encoded tool for structural manipulation of excitatory synapses
Problem links
provides a genetically encoded tool for structural manipulation of excitatory synapses
LiteratureIt addresses the lack of tools analogous to optogenetic and chemogenetic actuators for manipulating neural circuit structure rather than only activity.
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It addresses the lack of tools analogous to optogenetic and chemogenetic actuators for manipulating neural circuit structure rather than only activity.
Published Workflows
Objective: Develop a toolbox of genetically encoded synapse ablation tools for manipulating neural circuit structure by degrading synaptic scaffolding proteins at excitatory and inhibitory synapses, including constitutive, light-inducible, and chemically inducible variants.
Why it works: The workflow is based on rationally designing genetically encoded constructs that recruit degradation machinery to synaptic scaffolding proteins, so scaffold loss leads to functional synapse ablation.
E3 ligase-dependent degradation of synaptic scaffolding proteinsPSD-95-directed excitatory synapse ablationGephyrin-directed inhibitory synapse ablationrational designoptogenetic inductionchemogenetic induction
Taxonomy & Function
Primary hierarchy
Mechanism Branch
Architecture: A reusable architecture pattern for arranging parts into an engineered system.
Mechanisms
Degradatione3 ligase-dependent ubiquitin-mediated degradationproteasome-associated degradationtargeted protein degradationTechniques
Computational DesignTarget processes
degradationImplementation Constraints
cofactor dependency: cofactor requirement unknownencoding mode: genetically encodedimplementation constraint: context specific validationoperating role: regulatorswitch architecture: cleavage
The abstract indicates that PFE3 is genetically encoded and built from Mdm2 and Protocadherin 10-derived regions targeted to PSD-95. No delivery format or assay prerequisites are specified in the provided evidence.; uses an E3 ligase-dependent degradation mechanism; targets PSD-95 using Mdm2 and Protocadherin 10-derived functions
Independent follow-up evidence is still limited. Validation breadth across biological contexts is still narrow. Independent reuse still looks limited, so the evidence base may be fragile. No canonical validation observations are stored yet, so context-specific performance remains under-specified.
Validation
Cell-freeBacteriaMammalianMouseHumanTherapeuticIndep. Replication
Supporting Sources
Ranked Claims
chGFE3 is a chemically inducible GFE3 variant that degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim.
we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim.
paGFE3 is a light-inducible GFE3 variant based on a PhoCl2c photoactivatable complex that degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light.
we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light.
activation wavelength 400 nm
PFE3 targets Mdm2 RING and Protocadherin 10 proteasome-interacting functions to PSD-95, leading to efficient ablation of excitatory synapses.
PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses.
Each of the three synapse ablation tools is specific, reversible, and capable of breaking neural circuits at precise locations.
Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
The paper introduces three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to degrade synaptic scaffolding proteins and thereby functionally ablate synapses.
Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses.
Approval Evidence
1 source3 linked approval claimsfirst-pass slug pfe3
First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses.
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mechanism of actionsupports
PFE3 targets Mdm2 RING and Protocadherin 10 proteasome-interacting functions to PSD-95, leading to efficient ablation of excitatory synapses.
PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses.
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performance summarysupports
Each of the three synapse ablation tools is specific, reversible, and capable of breaking neural circuits at precise locations.
Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
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tool introductionsupports
The paper introduces three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to degrade synaptic scaffolding proteins and thereby functionally ablate synapses.
Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses.
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Comparisons
Source-stated alternatives
The abstract contrasts PFE3 with the inhibitory synapse ablator GFE3 and with inducible inhibitory variants paGFE3 and chGFE3.
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The abstract contrasts PFE3 with the inhibitory synapse ablator GFE3 and with inducible inhibitory variants paGFE3 and chGFE3.
Source-backed strengths
genetically encoded; specific; reversible; capable of breaking neural circuits at precise locations
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genetically encoded
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specific
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reversible
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capable of breaking neural circuits at precise locations
Compared with chGFE3
The abstract contrasts PFE3 with the inhibitory synapse ablator GFE3 and with inducible inhibitory variants paGFE3 and chGFE3.
Shared frame: source-stated alternative in extracted literature
Strengths here: genetically encoded; specific; reversible.
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The abstract contrasts PFE3 with the inhibitory synapse ablator GFE3 and with inducible inhibitory variants paGFE3 and chGFE3.
Compared with paGFE3
The abstract contrasts PFE3 with the inhibitory synapse ablator GFE3 and with inducible inhibitory variants paGFE3 and chGFE3.
Shared frame: source-stated alternative in extracted literature
Strengths here: genetically encoded; specific; reversible.
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The abstract contrasts PFE3 with the inhibitory synapse ablator GFE3 and with inducible inhibitory variants paGFE3 and chGFE3.
Ranked Citations
- 1.