Abstract
Phenylketonuria is a recessive genetic disorder of amino-acid metabolism, where impaired phenylalanine hydroxylase function leads to the accumulation of neurotoxic phenylalanine levels in the brain. Severe cognitive and neuronal impairment are observed in untreated/late-diagnosed patients, and even early treated ones are not safe from life-long sequelae. Despite the wealth of knowledge acquired from available disease models, the chronic effect of Phenylketonuria in the brain is still poorly understood and the consequences to the aging brain remain an open question. Thus, there is the need for better predictive models, able to recapitulate specific mechanisms of this disease. Human induced pluripotent stem cells (hiPSCs), with their ability to differentiate and self-organize in multiple tissues, might provide a new exciting in vitro platform to model specific PKU-derived neuronal impairment. In this review, we gather what is known about the impact of phenylalanine in the brain of patients and highlight where hiPSC-derived organoids could contribute to the understanding of this disease.
Highlights
Phenylketonuria (PKU; OMIM #261600) is a recessive genetic disorder of amino acid metabolism, affecting 1-5/10,000 individuals worldwide (ORPHANET, 2012)
We provide an overview on the current knowledge of PKU neuropathology and discuss the opportunity that induced pluripotent stem cells (iPSCs) represent in clarifying specific mechanisms involved in the reported mental and motor sequalae, by offering examples of engineered organoid models and their relevance in the context of this disease
Given the chronic nature of this disease, the complexity of the neuronal pathways affected and the possible relationship with neurodegenerative processes, it is of utmost importance to further clarify which mechanisms are involved, and how they are affected by high phenylalanine brain levels
Summary
Phenylketonuria is a recessive genetic disorder of amino-acid metabolism, where impaired phenylalanine hydroxylase function leads to the accumulation of neurotoxic phenylalanine levels in the brain. Despite the wealth of knowledge acquired from available disease models, the chronic effect of Phenylketonuria in the brain is still poorly understood and the consequences to the aging brain remain an open question. There is the need for better predictive models, able to recapitulate specific mechanisms of this disease. Human induced pluripotent stem cells (hiPSCs), with their ability to differentiate and self-organize in multiple tissues, might provide a new exciting in vitro platform to model specific PKU-derived neuronal impairment. We gather what is known about the impact of phenylalanine in the brain of patients and highlight where hiPSC-derived organoids could contribute to the understanding of this disease
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