Biochemical and behavioural profile of NTBC treated Tyrosinemie type 1 mice

Ginkel, Willem G. van; Winn, Shelley R.; Dudley, Sandra; Krenik, Destine; Perez, Ruby; Rimann, Nicole; Thöny, Beat; Raber, Jacob; Harding, Cary O.

doi:10.1016/j.ymgme.2022.07.001

Cited by 2 publications

(4 citation statements)

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“…To investigate the effects of phenylalanine and tyrosine levels on dopamine production, we exposed PC12 cells to different concentrations of these amino acids for periods of 1 to 6 and 1 to 24 hours, respectively. Serum phenylalanine levels 250-1000 µM are found in mild PKU (Van Wegberg et al, 2017), while the high concentrations of tyrosine used here (275-835 µM) reflect typical serum levels found in children treated with NTBC (Barone et al, 2020) and serum and brain tissue levels of NTBC treated mice (van Ginkel et al, 2022).…”

Section: Resultsmentioning

confidence: 67%

“…Uptake of L-Tyr is shown to increase proportionally to elevated external concentrations. Some recent animal studies show a close correlation between plasma and tissue levels of tyrosine (Davison et al, 2019; van Ginkel et al, 2022), however, some earlier studies on animals indicated that brain tyrosine concentrations do not exactly match plasma levels of L-Tyr (Berger et al, 1996; Harding et al, 2014).…”

Section: Discussionmentioning

confidence: 98%

“…Some studies concluded that artificially increased levels of L-Tyr raised L-Dopa production by TH without any apparent substrate inhibition (Brodnik et al, 2012; Wurtman et al, 1974), whereas others observed decreased catecholamine synthesis, possibly stemming from substrate inhibition (Badawy & Williams, 1982; Berger et al, 1996; DePietro & Fernstrom, 1998). To further complicate this picture, a recent study postulated that in the murine model of treated TYRSN1, monoamine neurotransmitter levels as well as behavioral and cognitive markers remained within normal parameters despite highly elevated tyrosine concentrations in the rat brain (van Ginkel et al, 2022). Earlier, Davison and colleagues arrived at a similar conclusion (Davison et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…As in humans, treatment of mice with NTBC increases tissue levels of tyrosine (van Ginkel et al, 2022). However, unlike in humans, where elevated plasma levels of tyrosine were associated with impaired cognitive functioning (Barone et al, 2020), no alterations in either behavior or brain monoamine levels were observed in this mouse model.…”

Section: Introductionmentioning

confidence: 99%

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The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria and tyrosinemia type 1

Szigetvari,

Patil,

Birkeland

et al. 2023

Preprint

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Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in phenylalanine accumulation and impaired tyrosine production. In Tyrosinemia type 1 (TYRSN1) mutations affect fumarylacetoacetate hydrolase, leading to accumulation of toxic intermediates of tyrosine catabolism. Treatment of TYRSN1 with nitisinone results in extreme tissue levels of tyrosine. Although PKU and TYRSN1 have opposite effects on tyrosine levels, both conditions have been associated with neuro-psychiatric symptoms indicative of impaired dopamine (DA) synthesis. However, concrete in vivo data on the possible molecular basis for disrupted DA production under disease mimicking conditions have been lacking. In pursuit to uncover associated molecular mechanisms, we exposed an established, DA producing cell line (PC12) to different concentrations of phenylalanine and tyrosine in culture media. We measured the effects on viability, proteomic composition, tyrosine, DA and tyrosine hydroxylase (TH) levels and TH phosphorylation. TH catalyzes the rate-limiting step in DA synthesis. High extracellular levels of phenylalanine rapidly depleted cells of intracellular tyrosine and DA. Compared to physiological levels (75 μM), either low (35 μM) or high concentrations of tyrosine (275 or 835 μM) decreased cellular DA, TH protein, and its phosphorylation levels. Using deep proteomic analysis, we identified multiple proteins, biological processes and pathways that were altered, including enzymes and transporters involved in amino acid metabolism. Specifically, levels of the broad specificity transporter of neutral amino acids LAT1 and the branched-chain amino-acid-transporter BCAT2 were both similarly increased. Using this information and published data, we developed a mathematical model to predict how extracellular levels of aromatic amino acids can affect the cellular synthesis of DA via different mechanisms. Together, these data provide new information about the normal regulation of neurotransmitter synthesis and how this may be altered on the molecular level in neurometabolic disorders, such as PKU and TYRSN1.

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Section: Resultsmentioning

confidence: 67%