Mechanistic Studies of cognitive impairment in Angelman syndrome

This study investigates how the ubiquitin E3 ligase UBE3A, whose deficiency causes Angelman syndrome (AS), regulates synaptic plasticity and cognitive function through the mTORC1 signaling pathway. The authors focus on p18 (LAMTOR1), a key component of the lysosomal Ragulator complex required for full mTORC1 activation.

Using biochemical, molecular, and electrophysiological approaches, the researchers show that UBE3A directly ubiquitinates p18, targeting it for proteasomal degradation. In the absence of UBE3A—as observed in the hippocampus of AS mouse models—p18 accumulates at lysosomes along with other Ragulator–Rag complex components, leading to abnormally elevated mTORC1 activity. This dysregulation disrupts key processes underlying neuronal development and function.

Functionally, excessive mTORC1 signaling in AS mice is associated with impaired dendritic spine maturation, deficits in long‑term potentiation (LTP), and compromised learning and memory. Importantly, targeted knockdown of p18 in hippocampal CA1 neurons normalizes mTORC1 activity and significantly rescues synaptic structure, synaptic plasticity, and behavioral performance.

These findings identify p18 as a critical molecular link between UBE3A deficiency and mTORC1 overactivation in Angelman syndrome. More broadly, the study demonstrates that precise regulation of lysosomal signaling complexes is essential for normal synaptic plasticity and cognitive function. The authors conclude that targeting components of the Ragulator–mTORC1 pathway may represent a promising therapeutic strategy for neurodevelopmental disorders characterized by aberrant mTOR signaling.