Antipsychotics Affect Satellite III (1q12) Copy Number Variations in the Cultured Human Skin Fibroblasts

Area of Science:

• Genetics
• Cell Biology
• Pharmacology

Background:

• Satellite III (f-SatIII) fragments reside in pericentromeric heterochromatin of chromosome 1.
• Enlarged f-SatIII blocks are associated with cellular stress susceptibility and unresponsiveness.
• f-SatIII levels in schizophrenia patients' cells fluctuate with antipsychotic treatment.

Purpose of the Study:

• To investigate the effect of common antipsychotics (haloperidol, risperidone, olanzapine) on f-SatIII content in human skin fibroblasts.
• To explore the correlation between f-SatIII levels, DNA damage, and cellular processes like apoptosis and autophagy.

Main Methods:

• Human skin fibroblast lines (n=10) were treated with antipsychotics for 3, 24, and 96 hours.
• f-SatIII DNA content was quantified using nonradioactive hybridization.
• RNA levels of f-SatIII (RNASATIII) were measured by RT-qPCR.
• DNA damage markers (8-oxodG, γ-H2AX) and apoptosis/autophagy proteins were analyzed via flow cytometry.

Main Results:

• Antipsychotics significantly reduced both f-SatIII DNA and RNASATIII RNA levels in fibroblasts.
• Autophagy marker LC3 increased, while apoptosis markers decreased following antipsychotic exposure.
• f-SatIII DNA content positively correlated with RNASATIII and DNA oxidation (8-oxodG), and negatively with LC3.

Conclusions:

• Antipsychotics inhibit f-SatIII repeat expansion in cultured fibroblasts.
• This inhibition appears to occur through transcriptional suppression and/or enhanced autophagy-mediated elimination of cells with enlarged f-SatIII blocks.