AMP‐activated protein kinase activation in mediating phenylalanine‐induced neurotoxicity in experimental models of phenylketonuria

Abstract

Phenylketonuria (PKU), one of the most prevalent autosomal recessive disorders of amino acid metabolism, is characterized by abnormal accumulation of phenylalanine, which can lead to intellectual disability. The main pathologic changes in the central nervous system of untreated phenylketonuric patients are reductions in the number of axons, dendrites, and synapses in the brain. Such alterations are thought to be mainly associated with the toxic effects caused by phenylalanine. However, the underlying molecular mechanisms have not been fully elucidated. The present study shows that a high concentration of phenylalanine remarkably inhibited neuronal neurite formation in vitro. Interestingly, AMP-activated protein kinase (AMPK), the energy status sensor, was activated in cultured cerebral cortical neurons upon phenylalanine treatment. Pretreatment with an AMPK inhibitor ameliorated the reduction of neurite formation caused by phenylalanine. In addition, the levels of the phosphorylated AMPK, the active form of AMPK, were significantly higher in the cerebral cortices of PKU mice with elevated phenylalanine levels in this brain region compared to those in wild-type control mice, whereas the density of dendritic spines on basal secondary dendrites of pyramidal neurons in prefrontal cortices of PKU mice was significantly decreased. Collectively, these findings indicate that AMPK activation is a key event in impaired neuronal dendritic development in PKU and consequently, a potential therapeutic target for developing neuroprotective strategies against phenylalanine-evoked brain injury in PKU.

Comparable Benefits of Stingless Bee Honey and Caffeic Acid in Mitigating the Negative Effects of Metabolic Syndrome on the Brain

“…It has also been suggested that phenylalanine in SBH may have a memory-enhancing effect, as it can act directly on BDNF to enhance brain and physiological signals [ 21 , 55 ]. Phenylalanine is an amino acid derived from the daily diet that is converted to tyrosine in the body, which is needed in the brain because it is a major constituent of the tyrosine kinase B receptor (TrkB) that acts as a BDNF receptor [ 56 ]. BDNF is a metabolic modulator in humans through dietary regulation, increased physical activity, and glucose metabolism [ 57 ].…”

Stingless Bee Honey Improves Spatial Memory in Mice, Probably Associated with Brain-Derived Neurotrophic Factor (BDNF) and Inositol 1,4,5-Triphosphate Receptor Type 1 (Itpr1) Genes

“…Observations from a previous study also highlighted the consistency of the phenylalanine in local stingless bee honey [33]. Phenylalanine is a dietary amino acid that is converted to tyrosine which occurs concurrently with the conversion of tetrahydrobiopterin to 4a-hydroxytetrahydrobiopterin and is catalysed by phenylalanine hydroxylase [43]. Tyrosine is needed in the brain as it is the main constituent of tyrosine receptor kinase B (TrkB) which plays a role as BDNF receptor.…”

Generation of urine-derived induced pluripotent stem cells from a patient with phenylketonuria

“…In addition, several studies have found that UiPSCs preferentially differentiate into neurons and that even epithelial-like cells from human urine can directly differentiate into neural progenitor cells (20,21). Although studies have suggested that irreversible nerve damage due to a high concentration of phenylalanine in the blood may be related to brain-derived neurotrophic factor (22,23), no studies have thoroughly examined the mechanism whereby hyperphenylalaninemia results in mental retardation. PKU-UiPSCs provide a useful approach with which to understand the neurological effects of PKU since UiPSCs differentiate into neurons and the ability to create key cell types not directly available from patients with PKU.…”