FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4386480922> ?p ?o ?g. }

• W4386480922 abstract "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. Highlights Tyrosinemia type I and phenylketonuria are rare metabolic disorders, characterized by extremely elevated plasma levels of the aromatic amino acids tyrosine and phenylalanine, respectively. To study the molecular consequences of dysregulated amino acid uptake on dopamine homeostasis, we simulated these conditions using rat pheochromocytoma (PC12) cells, an established model system for investigating catecholamine production. Non-physiological tyrosine levels induced a broad cellular response, including reduced protein level and phosphorylation stoichiometry for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, which in turn resulted in decreases in both intra- and extracellular dopamine levels. Similarly, dopamine content was also decreased when cells were exposed to high phenylalanine levels characteristic of phenylketonuria, although the underlying molecular mechanism for this response appears to differ." @default.
• W4386480922 created "2023-09-07" @default.
• W4386480922 creator A5008187218 @default.
• W4386480922 creator A5055442295 @default.
• W4386480922 creator A5058669350 @default.
• W4386480922 creator A5081698578 @default.
• W4386480922 creator A5092764212 @default.
• W4386480922 date "2023-09-05" @default.
• W4386480922 modified "2023-09-27" @default.
• W4386480922 title "The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria and tyrosinemia type 1" @default.
• W4386480922 cites W134599367 @default.
• W4386480922 cites W1497427077 @default.
• W4386480922 cites W1521199340 @default.
• W4386480922 cites W1596611034 @default.
• W4386480922 cites W1917032649 @default.
• W4386480922 cites W1967895335 @default.
• W4386480922 cites W1968297884 @default.
• W4386480922 cites W1972783241 @default.
• W4386480922 cites W1976407146 @default.
• W4386480922 cites W1977309516 @default.
• W4386480922 cites W1980506870 @default.
• W4386480922 cites W1986192026 @default.
• W4386480922 cites W1987823976 @default.
• W4386480922 cites W1992407636 @default.
• W4386480922 cites W1998234596 @default.
• W4386480922 cites W2007062022 @default.
• W4386480922 cites W2018098293 @default.
• W4386480922 cites W2021824487 @default.
• W4386480922 cites W2034419721 @default.
• W4386480922 cites W2037339156 @default.
• W4386480922 cites W2041038972 @default.
• W4386480922 cites W2044816246 @default.
• W4386480922 cites W2045299448 @default.
• W4386480922 cites W2050157124 @default.
• W4386480922 cites W2055665256 @default.
• W4386480922 cites W2055955248 @default.
• W4386480922 cites W2056584599 @default.
• W4386480922 cites W2066934153 @default.
• W4386480922 cites W2071411087 @default.
• W4386480922 cites W2073656121 @default.
• W4386480922 cites W2075349529 @default.
• W4386480922 cites W2076821664 @default.
• W4386480922 cites W2089317626 @default.
• W4386480922 cites W2094929193 @default.
• W4386480922 cites W2101113365 @default.
• W4386480922 cites W2102653059 @default.
• W4386480922 cites W2106610882 @default.
• W4386480922 cites W2109963281 @default.
• W4386480922 cites W2145611140 @default.
• W4386480922 cites W2153873971 @default.
• W4386480922 cites W2169887727 @default.
• W4386480922 cites W2279513999 @default.
• W4386480922 cites W2405467010 @default.
• W4386480922 cites W2460471412 @default.
• W4386480922 cites W2555472459 @default.
• W4386480922 cites W2608114095 @default.
• W4386480922 cites W2739965697 @default.
• W4386480922 cites W2761810763 @default.
• W4386480922 cites W2768262304 @default.
• W4386480922 cites W2778097043 @default.
• W4386480922 cites W2790783845 @default.
• W4386480922 cites W2900405160 @default.
• W4386480922 cites W2916098940 @default.
• W4386480922 cites W2950976066 @default.
• W4386480922 cites W2973574133 @default.
• W4386480922 cites W2982064264 @default.
• W4386480922 cites W2992862379 @default.
• W4386480922 cites W3028609772 @default.
• W4386480922 cites W3114320839 @default.
• W4386480922 cites W3160891568 @default.
• W4386480922 cites W3164152715 @default.
• W4386480922 cites W3200887787 @default.
• W4386480922 cites W3201865851 @default.
• W4386480922 cites W3213662384 @default.
• W4386480922 cites W4211039846 @default.
• W4386480922 cites W4252607676 @default.
• W4386480922 cites W4284968053 @default.
• W4386480922 cites W4294718981 @default.
• W4386480922 cites W57616982 @default.
• W4386480922 cites W993271046 @default.
• W4386480922 doi "https://doi.org/10.1101/2023.09.05.556372" @default.
• W4386480922 hasPublicationYear "2023" @default.
• W4386480922 type Work @default.
• W4386480922 citedByCount "0" @default.
• W4386480922 crossrefType "posted-content" @default.
• W4386480922 hasAuthorship W4386480922A5008187218 @default.
• W4386480922 hasAuthorship W4386480922A5055442295 @default.
• W4386480922 hasAuthorship W4386480922A5058669350 @default.
• W4386480922 hasAuthorship W4386480922A5081698578 @default.
• W4386480922 hasAuthorship W4386480922A5092764212 @default.
• W4386480922 hasBestOaLocation W43864809221 @default.
• W4386480922 hasConcept C11960822 @default.
• W4386480922 hasConcept C132154277 @default.
• W4386480922 hasConcept C134018914 @default.
• W4386480922 hasConcept C159167319 @default.
• W4386480922 hasConcept C181199279 @default.
• W4386480922 hasConcept C185592680 @default.
• W4386480922 hasConcept C207009774 @default.
• W4386480922 hasConcept C2776165026 @default.
• W4386480922 hasConcept C2776491826 @default.

• next