The E3 Ubiquitin Ligase PRAJA1: A Key Regulator of Synaptic Dynamics and Memory Processes with Implications for Alzheimer’s Disease

The precise regulation of synaptic function by targeted protein degradation is fundamental to learning and memory, yet the roles of many brain-enriched E3 ubiquitin ligases in this process remain elusive. Here, we uncover a critical and previously unappreciated role for the E3 ubiquitin ligase PRAJA1 in orchestrating synaptic plasticity and hippocampus-dependent memory. Utilizing C57BL/6 and 5xFAD male mice and employing a multi-faceted approach including protein biochemistry, molecular biology, in vitro electrophysiology, and behavioral assays, we demonstrate that long-term potentiation (LTP) induction triggers a rapid, proteasome-dependent downregulation of PRAJA1 within the CA1 region of the hippocampus. Critically, selective knockdown of PRAJA1 in vivo profoundly enhanced both object recognition and spatial memory, while disrupting normal exploratory behavior. Mechanistically, we reveal that PRAJA1 acts as a key regulator of synaptic architecture and transmission: its downregulation leads to a reduction in key synaptic proteins and spine density, influencing the excitatory/inhibitory balance and facilitating synaptic plasticity. Conversely, increased PRAJA1 expression potentiates GABAergic transmission. Furthermore, we identify spinophilin as a novel substrate of PRAJA1, suggesting a direct molecular link between PRAJA1 and synaptic remodeling. Strikingly, our findings implicate dysregulation of PRAJA1 in the pathogenesis of Alzheimer's disease, positioning PRAJA1 as a potential therapeutic target for cognitive enhancement in neurodegenerative conditions. These results unveil PRAJA1 as a critical molecular brake on synaptic plasticity and memory formation, offering a promising new avenue for understanding and potentially treating memory impairment.