Source 1primary paper2025MED
Toolkit/paGFE3
paGFE3
Taxonomy: Mechanism Branch / Architecture. Workflows sit above the mechanism and technique branches rather than replacing them.
Summary
In addition, 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.
Usefulness & Problems
Why this is useful
paGFE3 is a light-inducible inhibitory synapse ablator derived from GFE3. It degrades Gephyrin and ablates inhibitory synapses after 400 nm light exposure.; light-inducible ablation of inhibitory synapses; spatially precise manipulation of neural circuit structure
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paGFE3 is a light-inducible inhibitory synapse ablator derived from GFE3. It degrades Gephyrin and ablates inhibitory synapses after 400 nm light exposure.
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light-inducible ablation of inhibitory synapses
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spatially precise manipulation of neural circuit structure
Problem solved
It enables inducible and location-precise structural disruption of inhibitory synapses using light.; adds optical control to inhibitory synapse ablation
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It enables inducible and location-precise structural disruption of inhibitory synapses using light.
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adds optical control to inhibitory synapse ablation
Problem links
adds optical control to inhibitory synapse ablation
LiteratureIt enables inducible and location-precise structural disruption of inhibitory synapses using light.
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It enables inducible and location-precise structural disruption of inhibitory synapses using light.
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.
Techniques
Computational DesignTarget processes
degradationInput: Light
Implementation Constraints
cofactor dependency: cofactor requirement unknownencoding mode: genetically encodedimplementation constraint: context specific validationimplementation constraint: spectral hardware requirementoperating role: regulatorswitch architecture: cleavage
The abstract supports a requirement for genetic expression of the construct and 400 nm light illumination. It also states that the design uses a PhoCl2c-based photoactivatable complex.; requires 400 nm light; uses a photoactivatable complex based on PhoCl2c; acts through Gephyrin degradation
Needs compatible illumination hardware and optical access. 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 pagfe3
In addition, 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.
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mechanism of actionsupports
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.
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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 paGFE3 with constitutive PFE3 and chemically inducible chGFE3, and identifies it as a light-inducible version of GFE3.
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The abstract contrasts paGFE3 with constitutive PFE3 and chemically inducible chGFE3, and identifies it as a light-inducible version of GFE3.
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 paGFE3 with constitutive PFE3 and chemically inducible chGFE3, and identifies it as a light-inducible version of GFE3.
Shared frame: source-stated alternative in extracted literature
Strengths here: genetically encoded; specific; reversible.
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The abstract contrasts paGFE3 with constitutive PFE3 and chemically inducible chGFE3, and identifies it as a light-inducible version of GFE3.
Compared with PFE3
The abstract contrasts paGFE3 with constitutive PFE3 and chemically inducible chGFE3, and identifies it as a light-inducible version of GFE3.
Shared frame: source-stated alternative in extracted literature
Strengths here: genetically encoded; specific; reversible.
Source:
The abstract contrasts paGFE3 with constitutive PFE3 and chemically inducible chGFE3, and identifies it as a light-inducible version of GFE3.
Ranked Citations
- 1.