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Breakthrough Study Reveals Key Mechanism Underlying ZC4H2-Associated Intellectual Disability and Potential Therapeutic Target
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2025-07-21

Recently, a groundbreaking study published 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. The research, led by Dr. MAO Bingyu and colleagues from the Kunming Institute of Zoology, Chinese Academy of Sciences, 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 indicated that ZC4H2 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 indicated 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.

 

Additionaly, this study provided evidence to support that Perampanel, a PDA proved drug, showed a strong potential for ZARD therapy. In a mouse model of ZARD, the clinically approved AMPAR antagonist perampanel normalized synaptic overactivity and restored cognitive functions, including recognition memory, social memory, and spatial learning. Remarkably, behavioral improvements occurred despite persistent AMPAR trafficking defects, highlighting the drug’s ability to compensate for underlying molecular dysfunction. Therefore, the findings position AMPAR modulation as a promising strategy for ZARD and other intellectual disability disorders with similar synaptic pathologies. Perampanel, already used for epilepsy, could be repurposed to address cognitive symptoms in ZARD patients.

 

“Our work bridges a critical gap between genetic mutations and synaptic dysfunction in ZARD, and by pinpointing AMPAR hyperactivity as the culprit, we’ve identified a druggable target with immediate clinical relevance.” the researchers noted.

 

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


Contact:

Dr. MA Pengcheng

Kunming Institute of Zoology, Chinese Academy of Sciences,

Kunming, Yunnan 650201, China

E-mail: kunmapch@mail.kiz.ac.cn

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