STON2 Variations Linked to Schizophrenia-Like Behaviors

Science China Press

This study is led by Prof. Jun Li (Peking University Sixth hospital), Prof. Dai Zhang (Peking University Sixth hospital), Dr. Yuanlin Ma (Peking University Sixth hospital; The First Affiliated Hospital of Chongqing Medical University), and Dr. Kai Gao (Peking University Sixth hospital; Changping Laboratory).

Schizophrenia is a severe mental disorder characterized by positive symptoms, negative symptoms and cognitive deficits, with heritability estimates of approximately 80%. Synaptic dysfunction is a core component of the pathophysiology of schizophrenia. However, the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.

Clathrin-mediated endocytosis (CME) plays a crucial role in synaptic vesicle trafficking, and it has been hypothesized that CME impairment contributes to neuropathology related to schizophrenia. Ma et al. found that the C-C (307Pro-851Ala) haplotype of STON2 increases susceptibility to schizophrenia in Chinese Han population and these variations cause schizophrenia-like behaviors in mice through the regulation of CME.

They revealed that schizophrenia-related STON2 variations led to protein dephosphorylation, which affected the interaction of the protein with synaptotagmin 1 (Syt1), a calcium sensor protein located in the presynaptic membrane that is critical for CME. STON2^307Pro851Ala knockin mice exhibited deficits in synaptic transmission, short-term plasticity and schizophrenia-like behaviors. Moreover, Pharmacogenomic data revealed that patients with the C-C (307Pro-851Ala) haplotype responded better to haloperidol, and haloperidol administration restored the schizophrenia-related behaviors of STON2^307Pro851Ala knock in mice through the regulation of Syt1 sorting and synaptic transmission.

Their findings demonstrated the effect of schizophrenia-related STON2 variations on CME and synaptic function, which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.

See the article:

STON2 variations are involved in synaptic dysfunction and schizophrenia-like behaviors by regulating Syt1 trafficking

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