Cognitive impairment and psychiatric disturbances are still observable in a consistent minority of early and continuously treated adult PKU (ECTPKU) patients and there is increasing evidence that individual brain sensitivity to hyperphenylalaninemia (HPA) contributes to this variability. The identification of markers of HPA sensitivity will allow for a personalized/precision medicine approach to PKU capable of preventing costs and potential dangers of life-long treatment of healthy ECTPKU adult. The proposed research is part of a larger project aimed at integrating cognitive, physiological, and neuroimaging data from adult patients and behavioral and neurobiological data from animal models to identify reliable markers of life-long sensitivity to pathogenic effects of HPA.
Mice from two PKU models that mimic the metabolic disease through a chemically induced point mutation in the gene encoding for PAH: the BTBR PHA-enu2 and the C57BL/6 (B6) PHA-enu2 wil be used. The two models differ for the genetic background on which the mutation is expressed and severity of the cognitive dysfunctions but not for brain phenylalanine (Phe) levels. Research plans and protocols are based on findings obtained by proponents' previous studies in adult EPKU patients and BTBR PHA-enu2 mice and focus on the aminergic stress response by the pre-Frontal cortex (pFC) because of its involvement in development and expression of depression and anxiety, the most diffused behavioral disturbances reported in ECTPKU adult patients. Intra-cerebral microdyalisis in freely-moving mice will be used to evaluate pFC response to stress and performance in stress-associated learning tests will be used to evaluate adaptation to challenging experiences by adult PHA-enu2 mice of the two backgrounds. Search for associated biomarkers will be both hypothesis-driven and based on blood transcriptome profiling of mice from the two PKU models.
Results obtained by the proposed project will progress the understanding of the neuropathogenesis fostered by HPA in classic PKU as well as in other HPA-dependent disturbances, placing the bases for development of a personalized approach to the disease.
The research proposed is innovative because it targets mechanisms responsible for individual sensitivity to HPA rather than those responsible for HPA. Both clinical and animal studies on this topic, are extremely rare.
The project is innovative because it searches for the neurobiological mechanisms responsible of HPA-induced neuropsychiatric disturbances. Anxiety and depression are reported by up to half of adult PKU patients in survey data and the incidence of these disturbances is significantly higher among adults with PKU than the general population. However, direct exploration of the involved mechanisms, which requires specific studies in animal models, has not yet been a topic of research.
The project is innovative because it stems from the hypothesis that it is possible to discriminate individual variations in brain vulnerability to Phe by the use of specific blood biomarkers. Blood biomarkers are easily accessible clinically, as opposed to brain imaging or even CSF changes, and have been successfully used as biomarkers for depression, suicide risk, and stress susceptibility.