Impaired Activity-Regulated Proteostasis: A Shared Mechanism in Neurodevelopmental Disorders

Proteostasis is the process by which cells control how much of each protein is made, how long it persists, and when it is removed. In neurons, proteostasis is not merely a housekeeping function, it is actively regulated by neuronal activity. When neurons fire, protein synthesis and degradation are simultaneously and transiently regulated to support synaptic plasticity. In neurodevelopmental disorders (NDDs), neurons lose this capacity to dynamically regulate their proteome in response to stimulation, disrupting synaptic plasticity and leading to cognitive impairments. This review establishes that despite diverse genetic origins, failure of activity-regulated proteostasis is a shared vulnerability across NDDs. This also explains why increasing or blocking protein synthesis or degradation alone under basal condition is insufficient to restore normal function. Our work demonstrates that restoring the coupling between neuronal activity and proteostatic response rescues both molecular and cognitive impairments in NDDs. These findings open new avenues for investigating disease biology and for developing novel therapeutic strategies.