A new study published on July 9 in PNAS uncovers the critical role of the protein ZC4H2 in regulating synaptic activity and cognitive function, offering new hope for treating ZC4H2-associated rare disorder (ZARD), a debilitating neurodevelopmental condition. 

Led by Dr. MAO Bingyu and his colleagues from the Kunming Institute of Zoology of the Chinese Academy of Sciences, the study identifies aberrant AMPA receptor (AMPAR) activity as a key driver of intellectual disability in ZARD and demonstrates the therapeutic potential of the AMPAR antagonist perampanel.

Key Findings indicate that ZC4H2 acts as a synaptic regulator. In vivo TurboID proximity labeling analysis suggest that, in additon to ribosome/translation, RNA bingding/metabolism, and cytoskeleton/kinase, ZC4H2 was involved in glutamatic synapse/recetpors protein network. 

Further biochemical analysis revealed that ZC4H2 directly interacts with AMPARs at postsynaptic sites, controlling their ubiquitination and stability. Loss of ZC4H2 leads to excessive AMPAR accumulation, hyperactive synaptic transmission, and impaired long-term potentiation (LTP), a process essential for learning and memory.

Additionally, the researchers provided evidence supporting the strong potential of perampanel, a PDA-approved drug, for ZARD therapy. In a mouse model of ZARD, the AMPAR antagonist perampanel, which is approved for clinical use, normalized synaptic overactivity and restored cognitive functions, including recognition memory, social memory, and spatial learning. Remarkably, these behavioral improvements occurred despite persistent AMPAR trafficking defects, highlighting the drug's ability to compensate for underlying molecular dysfunction. 

Therefore, these findings suggest that modulating AMPARs is a promising strategy for treating ZARD and other intellectual disability disorders with similar synaptic pathologies. Since perampanel is already used to treat epilepsy, it could be repurposed to address cognitive symptoms in ZARD patients.

"This work bridges a critical gap between genetic mutations and synaptic dysfunction in ZARD, by pinpointing AMPAR hyperactivity as the culprit, we have identified a druggable target with immediate clinical relevance," said Dr. MAO.

This work was supported by the National Key R&D Program of China and the National Natural Science Foundation of China, etc.