In ALS, chronic ISR activation creates an eIF2α~P state that represses axonal protein synthesis below synaptic maintenance thresholds, causing NMJ denervation. Analogously, in TDP-43-type FTD, chronic ISR activation driven by TDP-43 aggregates and proteostatic stress may repress local dendritic/synaptic protein synthesis required for glutamatergic synapse stability, contributing to early cortical synaptic loss and frontotemporal network dysfunction. The prediction is that cortical neurons in FTD
Radar Chart — 10 Dimensions
Score Comparison Bars
Mechanistic
0.60
Evidence
0.65
Novelty
0.70
Feasibility
0.00
Impact
0.00
Druggability
0.00
Safety
0.00
Competition
0.00
Data
0.00
Reproducible
0.00
KG Connect
0.50
Score Breakdown
Dimension
ISR/eIF2α~P Overflow Represses
Mechanistic
0.600
Evidence
0.650
Novelty
0.700
Feasibility
0.000
Impact
0.000
Druggability
0.000
Safety
0.000
Competition
0.000
Data
0.000
Reproducible
0.000
KG Connect
0.500
Evidence
ISR/eIF2α~P Overflow Represses Synaptic Proteostasis in Cort