Therapeutic effect of histone deacetylase 6 inhibitor for a mouse model of phenylketonuria

Abstract

Abstract Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutations in the phenylalanine hydroxylase ( PAH ) gene, leading to phenylalanine accumulation and clinical symptoms such as intellectual disability and hypopigmentation. Histone deacetylase 6 inhibitors (HDAC6i), known to promote the degradation of misfolded proteins, have shown potential in treating protein misfolding-related disorders. In this study, we evaluated the therapeutic effect of Tubastatin A, a selective HDAC6i, in Pah eun2 PKU model mice carrying a missense PAH mutation. Mice were treated with Tubastatin A for 12 weeks, and outcomes were assessed via phenylalanine levels, fur pigmentation, and expression of heat shock protein 90 (HSP90). Treated mice exhibited approximately a 50% reduction in plasma phenylalanine levels, partial recovery of black fur pigmentation, and increased expression of acetylated HSP90 in the liver. These findings suggest that HDAC6 inhibition may alleviate PKU symptoms by increasing HSP90 acetylation, which interferes with the degradation of misfolded PAH and may allow residual enzymatic activity. Our results support the therapeutic potential of HDAC6i in PKU and warrant further studies to optimize dosage and evaluate the long-term effects and safety of sustained treatment.