ISR/eIF2α~P Overflow Represses Synaptic Proteostasis in Cortical Neurons in TDP-43-Type Frontotemporal Dementia

h-analogy-7609ce00

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