Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria

Manek, Rachna; Zhang, Yao V; Berthelette, Patricia; Hossain, Mahmud; Cornell, Cathleen S.; Gans, Joseph H.; Anarat-Cappillino, Gulbenk; Geller, Sarah; Jackson, Robert; Yu, Dan; Singh, Kuldip; Ryan, Sue; Bangari, Dinesh S.; Kyostio-Moore, Sirkka

doi:10.1038/s41598-021-02267-2

Cited by 13 publications

(4 citation statements)

References 43 publications

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“…2 A ), suggesting that aspartame’s effects may extend beyond the glutamate-GABA axis and involve dopaminergic signaling in the amygdala. Aspartame’s effects on dopamine could occur as a result of increases in plasma and brain concentrations of phenylalanine ( 3 – 5 , 11 , 69 – 71 ), another metabolite of aspartame. However, since our focus was on the glutamatergic and GABAergic neurotransmission, we did not pursue further the changes in dopaminergic synapse pathway.…”

Section: Discussionmentioning

confidence: 99%

Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala

Jones

McCarthy

Vied

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D ( Grin2d ) and metabotropic receptor 4 ( Grm4 ) and downregulation of the GABA-A receptor associated protein ( Gabarap ) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame’s potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.

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Section: Discussionmentioning

confidence: 99%

Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala

Jones

McCarthy

Vied

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…It is likely that with the reduction in cost and wide application of NGS, newborn genetic screening has recently received more attention [ 121 – 125 ]. Multiple studies have assessed the effect of HPA on liver functions in PKU in mice using transcriptome and proteomic analyses [ 126 ].…”

Section: Molecular Diagnosismentioning

confidence: 99%

Genetic etiology and clinical challenges of phenylketonuria

et al. 2022

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This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. The prevalence of PKU varies widely among ethnicities and geographic regions, affecting approximately 1 in 24,000 individuals worldwide. Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). Severe phenotypes are classic PKU, and less severe forms of PAH deficiency are moderate PKU, mild PKU, mild hyperphenylalaninaemia (HPA), or benign HPA. Early diagnosis and intervention must start shortly after birth to prevent major cognitive and neurological effects. Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120–360 μmol/L throughout the life span. Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. The synthetic BH4 analog, sapropterin hydrochloride (i.e., Kuvan®, BioMarin), is another potential treatment that activates residual PAH, thus decreasing Phe concentrations in the blood of PKU patients. Moreover, daily subcutaneous injection of pegylated Phe ammonia-lyase (i.e., pegvaliase; PALYNZIQ®, BioMarin) has promised gene therapy in recent clinical trials, and mRNA approaches are also being studied.

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“…Another potential therapy (currently in clinical trials Phase 1/2) consists of a single delivery of a rAAV carrying the PAH gene directly into liver to convert Phe into tyrosine, mimicking the normal process of Phe metabolism. In 2021, Manek et al [ 80 ] performed transcriptomic and proteomic analyses in order to compare these two Phe-lowering strategies. They found that both approaches lower brain Phe and increase neurotransmitter levels, thereby correcting animal behavior.…”

Section: Proteomics For the Study Of Imdmentioning

confidence: 99%

Proteomics in Inherited Metabolic Disorders

Chantada-Vázquez

Bravo

Gouveia

et al. 2022

IJMS

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Inherited metabolic disorders (IMD) are rare medical conditions caused by genetic defects that interfere with the body’s metabolism. The clinical phenotype is highly variable and can present at any age, although it more often manifests in childhood. The number of treatable IMDs has increased in recent years, making early diagnosis and a better understanding of the natural history of the disease more important than ever. In this review, we discuss the main challenges faced in applying proteomics to the study of IMDs, and the key advances achieved in this field using tandem mass spectrometry (MS/MS). This technology enables the analysis of large numbers of proteins in different body fluids (serum, plasma, urine, saliva, tears) with a single analysis of each sample, and can even be applied to dried samples. MS/MS has thus emerged as the tool of choice for proteome characterization and has provided new insights into many diseases and biological systems. In the last 10 years, sequential window acquisition of all theoretical fragmentation spectra mass spectrometry (SWATH-MS) has emerged as an accurate, high-resolution technique for the identification and quantification of proteins differentially expressed between healthy controls and IMD patients. Proteomics is a particularly promising approach to help obtain more information on rare genetic diseases, including identification of biomarkers to aid early diagnosis and better understanding of the underlying pathophysiology to guide the development of new therapies. Here, we summarize new and emerging proteomic technologies and discuss current uses and limitations of this approach to identify and quantify proteins. Moreover, we describe the use of proteomics to identify the mechanisms regulating complex IMD phenotypes; an area of research essential to better understand these rare disorders and many other human diseases.

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Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria

Cited by 13 publications

References 43 publications

Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala

Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala

Genetic etiology and clinical challenges of phenylketonuria

Proteomics in Inherited Metabolic Disorders

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