PhD grants "Study of the effects of hyperphenylalaninemia on neurocognitive functions in a mouse model of adult phenylketonuria" (SSBCV)

• 36 months doctoral funding (October 2021 to September 2024)
• Keywords

phenylketonuria, cognitive functions, metabolomics, neuroinflammation

• Profile and skills required

Neuroscience

Molecular biology

Biochemistry

Animal experiment

Metabolism and nutrition

Level of French required: Advanced: You can speak the language in a more complex, spontaneous way and on a variety of subjects.

Level of English required: Upper Intermediate: You can use the language effectively and express yourself accurately.

• Project description

Phenylketonuria (PKU) is linked to a genetic deficiency of phenylalanine hydroxylase (PAH), which is an enzyme that metabolizes phenylalanine (Phe) into tyrosine. The loss of enzyme activity leads to an increase in Phe in both blood and brain which, if untreated, is responsible for severe neurological damage and therefore developmental delay. Treatment of screened newborns is neuroprotective; it is based on a low-Phe diet with the goal of plasma Phe <360 µmol/L. However, the outcome is considered as suboptimal in adults with PKU. They can indeed have neurocognitive disorders which can be related to metabolic fluctuations in childhood or linked to a chronic hyperPhe toxicity on the adult brain (hence the recommendation to maintain plasma Phe <600 µmol / L for life, from the age of 12y). Our objectives are to show that hyperPhe remains toxic to the brain of affected adults and to characterize the mechanisms of specific neurocognitive disorders in adulthood, based on our previous works that have shown 1) a correlation between hyperPhe and cognitive impairment (IQ, executive functions) in a national cohort of adult PKU patients (national PHRC ECOPHEN, article in press 2) a disruption of the kynurenin pathway whose metabolites are neurotoxic or proinflammatory. We also assume that there is also a systemic inflammation (INGRAPH study, ongoing). To confirm our hypotheses, we propose to carry out a longitudinal phenotyping of neurocognitive impairment in a mouse model of PKU (Pahenu2/enu2 mice) and to characterize the underlying mechanisms of hyperPhe neurotoxicity by a metabolomic approach, a targeted approach to the kynurenin pathway (linked to gut microbiote) and research of neuroinflammation.

• References

Phenylketonuria. Blau N, van Spronsen FJ, Levy HL Lancet 2010;376:1417-27.

Adult phenylketonuria outcome and management. Trefz F, Maillot F, Motzfeldt K, Schwarz M. Mol Genet Metab. 2011;104 Suppl:S26-30.

Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Enns GM, Koch R, Brumm V, Blakely E, Suter R, Jurecki E. Mol Genet Metab 2010;101:99-109.

Key European guidelines for the diagnosis and management of patients with phenylketonuria. van Spronsen FJ, van Wegberg AM, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, Trefz FK, van Rijn M, Walter JH, MacDonald A. Lancet Diabetes Endocrinol. 2017;5:743-56.

Tryptophan metabolism in phenylketonuria: A French adult cohort study. Boulet L, Besson G, Van Noolen L, Faure P; ECOPHEN Study Group, Maillot F, Corne C. J Inherit Metab Dis. 2020;43:944-51.

Long-Term Follow-Up of Cognition and Mental Health in Adult Phenylketonuria: A PKU-COBESO Study. Jahja R, van Spronsen FJ, de Sonneville LMJ, van der Meere JJ, Bosch AM, Hollak CEM, Rubio-Gozalbo ME, Brouwers MCGJ, Hofstede FC, de Vries MC, Janssen MCH, van der Ploeg AT, Langendonk JG, Huijbregts SCJ. Behav Genet. 2017;47:486-97.

Phenylalanine effects on brain function in adult phenylketonuria. Pilotto A, Zipser CM, Leks E, Haas D, Gramer G, Freisinger P, Schaeffer E, Liepelt-Scarfone I, Brockmann K, Maetzler W, Schulte C, Deuschle C, Hauser AK, Hoffmann GF, Scheffler K, van Spronsen FJ, Padovani A, Trefz F, Berg D. Neurology. 2020 Oct 22:10. Online ahead of print

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