Phenylketonuria (PKU; OMIM #261600) is an inborn error of amino acid metabolism due to the defect of the phenylalanine hydroxylase (PAH) enzyme that converts phenylalanine (Phe) into tyrosine. The introduction of newborn screening programs and the early start of dietary treatment radically changed the natural history of PKU. However, clinical outcome of early treated PKU patients is suboptimal because patients still disclose lower intelligence quotient, minor neuropsychological and psychiatric problems which remain challenging aspects of the disease and the possible targets for future improvement of the treatment.
Although several mechanisms, such as impairment in synaptic plasticity, neurotransmission, myelination, protein synthesis, energy metabolism, oxidative stress, and amyloid fibrils have been hypothesized, the pathophysiology of the neurological damage in PKU is still unknown. A big help in elucidating those mechanisms was given from the development of a genetic mouse model for PKU, the BTBR-ENU2 mouse (ENU2). Previous studies on ENU2 mouse showed that hyperphenylalaninemia interfere with brain tryptophan hydroxylase activity by reducing the availability of 5-HT, and that cortical spine maturation, and consequently cognitive deficits, are affected in ENU2 mice through a 5-HT-dependent pathway.
To date, the role of specific 5-HT receptor subtypes in the cognitive and behavioral profile of ENU2 mice has not been thoroughly investigated. Therefore, part I of present project will evaluate the cellular and molecular components that are altered during ENU2 mice development and adult life, with particular attention to serotoninergic pathway. This will allow finding suitable therapeutic windows to counteract cognitive delay in PKU adult affected patients.
In the second part of the project, which has a translational value, peripheral serotonin will be investigated in PKU patients with the aim of finding a predictive biomarker of neurocognitive dysfunction.
