TNIK influence the effects of antipsychotics on Wnt/β-catenin signaling pathway

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Traf2- and Nck-interacting kinase (TNIK), a germinal center kinase (GCK) family member, is linked to schizophrenia, bipolar disorder, and antipsychotic drug action.
• TNIK activates the Wnt/β-catenin signaling pathway, which is implicated in the mechanisms of antipsychotic effects.

Purpose of the Study:

• To investigate how altering Traf2- and Nck-interacting kinase (TNIK) expression affects Wnt/β-catenin signaling proteins.
• To determine the role of TNIK in the cellular response to antipsychotics like clozapine and risperidone.

Main Methods:

• Human glioma U251 cells were used to examine the impact of TNIK (upregulated or downregulated via siRNA) on β-catenin, T-cell factor 4 (TCF-4), glycogen synthase kinase-3β (GSK3β), and phosphorylated GSK3β (p-GSK3β).
• The effects of clozapine and risperidone on these proteins were observed, and the influence of differential TNIK expression on antipsychotic-treated cells was evaluated.

Main Results:

• Clozapine reduced β-catenin and TCF-4 levels; risperidone decreased β-catenin and p-GSK3β levels in U251 cells.
• Downregulating TNIK using siRNA hindered antipsychotics' regulation of Wnt pathway proteins by increasing TCF-4, β-catenin, or p-GSK3β expression.
• Upregulating TNIK did not produce significant changes in the observed Wnt pathway proteins.

Conclusions:

• Traf2- and Nck-interacting kinase (TNIK) plays a role in mediating the effects of antipsychotics, potentially through its influence on the Wnt/β-catenin signaling pathway.
• Modulating TNIK expression, particularly downregulation, affects the cellular response to antipsychotics, highlighting its involvement in treatment mechanisms.