ISR/eIF2α~P Overflow Represses Synaptic Protein Synthesis Downstream of Tau/Aβ Pathology in Alzheimer's Disease

h-analogy-8b267076

In ALS motor neurons, chronic ISR activation via proteostatic stress from TDP-43/FUS aggregates creates a pathological eIF2α~P state that represses axonal protein synthesis below the threshold for synaptic maintenance. In AD, we analogize that tau hyperphosphorylation and Aβ oligomerization similarly induce chronic ISR activation (via PERK/GCN2/PKR), creating eIF2α~P overflow that represses local