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

Oscar Aubi, Karina S. Prestegård, Kunwar Jung-KC, Tie-Jun Sten Shi, Ming Ying, Ann Kari Grindheim, Tanja Scherer, Arve Ulvik, Adrian McCann, Endy Spriet, Beat Thöny and Aurora Martinez ()
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Oscar Aubi: University of Bergen
Karina S. Prestegård: University of Bergen
Kunwar Jung-KC: University of Bergen
Tie-Jun Sten Shi: University of Bergen
Ming Ying: University of Bergen
Ann Kari Grindheim: University of Bergen
Tanja Scherer: University Children’s Hospital Zürich and Children’s Research Centre
Arve Ulvik: Bevital AS, Laboratoriebygget
Adrian McCann: Bevital AS, Laboratoriebygget
Endy Spriet: University of Bergen
Beat Thöny: University Children’s Hospital Zürich and Children’s Research Centre
Aurora Martinez: University of Bergen

Nature Communications, 2021, vol. 12, issue 1, 1-16

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

Date: 2021
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DOI: 10.1038/s41467-021-22107-1

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