BBB seminar: Cary O. Harding

Cary O. Harding
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA

Phenylalanine hydroxylase (PAH) deficiency, colloquially known as phenylketonuria (PKU), is among the most common, earliest known, and most studied inborn errors of metabolism, yet the precise pathophysiology that explains the effects of phenylalanine (Phe) excess upon the brain remain incompletely understood. We have employed the Pah^enu2 mouse, a model of human PAH deficiency, to explore aspects of the neurocognitive, behavioral, pathologic, and metabolic phenotype in murine PKU. The Pah^enu2 mouse is a model of untreated human PKU; typically we cannot initiate Phe lowering treatments until after weaning, by which time irreversible damage to the developing brain has already occurred. The brain is small in size, and neuropathologic examination reveals normal neuron numbers but disturbed dendritic branching and decreased synaptic connections. These findings are not different than those from rare neuropathologic evaluations of humans with untreated PKU. We find fixed partial deficits in brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH2) expression, yet the accompanying deficits in brain dopamine and serotonin content are completely reversible in adult mice upon initiation of Phe-lowering treatment such as dietary Phe restriction or liver-directed gene therapy with restoration of liver PAH expression. These data demonstrate that the predominant mechanism causing dopamine and serotonin deficiency is likely Phe-mediated competitive inhibition of TH and TPH2 activities; once brain Phe concentrations are lowered, TH and TPH2 activities are restored and the production of monoamines resumes. Behaviorally, exhibiting a phenotype similar to symptoms experienced by many human adults with elevated blood Phe, hyperphenylalaninemic mice exhibit increased anxiety in the open field. Most strikingly however, the animals exhibit severely impaired memory as assessed in a Morris water maze or by novel object recognition. Interestingly, the open field anxiety is reversible with Phe-lowering treatment initiated during adulthood but the memory deficit remains immutable.

Pegvaliase is a novel and successful enzyme substitution therapy that has been recently approved in the US and EU for treatment of adults with PAH deficiency. We have been exploring the effects of pegvaliase treatment initiated in Pah^enu2 mice initiated shortly after birth and continued into adulthood to determine its effect upon the hyperphenylalaninemic phenotype of these mice. Our goal is to develop a model of early treated human PKU. Our preliminary data suggest that we have been able to maintain near normal blood and brain Phe concentrations in the mice throughout the lifespan. As adults, the mice exhibit cognition and behavior indistinguishable from that of their wild type littermates suggesting that treatment from birth has successfully prevented the early brain damage associated with the untreated model. Pathologic and metabolic characterization of early treated animals continues.

Chairperson: Aurora Martinez, Department of Biomedicine