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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 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.

SUBMITTER: Aubi O

PROVIDER: S-EPMC8024259 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Phenylalanine hydroxylase (PAH) deficiency is one of 31 targeted inherited metabolic diseases (IMD) for the Canadian Inherited Metabolic Diseases Research Network (CIMDRN). Early diagnosis and initiation of treatment through newborn screening has gradually shifted treatment goals from the prevention of disabling complications to the optimization of long term outcomes. However, clinical evidence demonstrates that subtle suboptimal neurocognitive outcomes are present in the early and continuously diet-treated population with PAH deficiency. This may be attributed to variation in blood phenylalanine levels to outside treatment range and this, in turn, is possibly due to a combination of factors; disease severity, dietary noncompliance and differences in practice related to the management of PAH deficiency. One of CIMDRN's goals is to understand current practices in the diagnosis and management of PAH deficiency in the pediatric population, from the perspective of both health care providers and patients/families. OBJECTIVES:We investigated Canadian metabolic dietitians' perspectives on the nutritional management of children with PAH deficiency, awareness of recently published North American treatment and nutritional guidelines in relation to PAH deficiency, and nutritional care practices within and outside these guidelines. METHODS:We invited 33 dietitians to participate in a survey, to ascertain their use of recently published guidelines and their practices in relation to the nutritional care of pediatric patients with PAH deficiency. RESULTS:We received 19 responses (59% response rate). All participants reported awareness of published guidelines for managing PAH deficiency. To classify disease severity, 89% of dietitians reported using pre-treatment blood phenylalanine (Phe) levels, alone or in combination with other factors. 74% of dietitians reported using blood Phe levels ?360??mol/L (6?mg/dL) as the criterion for initiating a Phe-restricted diet. All respondents considered 120-360??mol/L (2-6?mg/dL) as the optimal treatment range for blood Phe in children 0-9?years old, but there was less agreement on blood Phe targets for older children. Most dietitians reported similar approaches to diet assessment and counseling: monitoring growth trends, use of 3?day diet records for intake analysis, individualization of diet goals, counseling patients to count grams of dietary natural protein or milligrams of dietary Phe, and monitoring blood Phe, tyrosine and ferritin. CONCLUSION:While Canadian dietitians' practices in managing pediatric PAH deficiency are generally aligned with those of the American College of Medical Genetics and Genomics (ACMG), and with the associated treatment and nutritional guidelines from Genetic Metabolic Dietitians International (GMDI), variation in many aspects of care reflects ongoing uncertainty and a need for robust evidence.

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

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