The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase

Abstract Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase ( PAH ), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah - R261Q mouse, with a highly prevalent misfolding variant humans, reveals the expected hepatic activity decrease, L-Phe increase, L-tyrosine and L-tryptophan tetrahydrobiopterin-responsive hyperphenylalaninemia. mice also present unexpected traits, including altered lipid metabolism, reduction liver tetrahydrobiopterin content, metabolic profile indicative oxidative stress. Pah-R261Q tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates mutant colocalize selective autophagy markers. Together, these findings reveal PKU, customarily considered loss-of-function disorder, can have toxic gain-of-function contribution from protein aggregation. The proteostasis defect concomitant stress explain prevalence comorbid conditions adult PKU patients, placing this mouse model an advantageous position for discovery mutation-specific biomarkers therapies.