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• W1564508078 endingPage "437" @default.
• W1564508078 startingPage "426" @default.
• W1564508078 abstract "Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopamine neurons of the nigrostriatal system, resulting in severe motor disturbances. Although much less appreciated, non-motor symptoms are also very common in PD and many can be traced to serotonin neuronal deficits. Tryptophan hydroxylase (TPH) 2, the rate-limiting enzyme in the serotonin biosynthesis, is a phenotypic marker for serotonin neurons and is known to be extremely labile to oxidation. Therefore, the oxidative processes that prevail in PD could cause TPH2 misfolding and modify serotonin neuronal function much as is seen in dopamine neurons. Oxidation of TPH2 inhibits enzyme activity and leads to the formation of high molecular weight aggregates in a dithiothreitol-reversible manner. Cysteine-scanning mutagenesis shows that as long as a single cysteine residue (out of a total of 13 per monomer) remains in TPH2, it cross-links upon oxidation and only cysteine-less mutants are resistant to this effect. The effects of oxidants on TPH2 catalytic function and cross-linking are also observed in intact TPH2-expressing HEK293 cells. Oxidation shifts TPH2 from the soluble compartment into membrane fractions and large inclusion bodies. Sequential non-reducing/reducing 2-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting confirmed that TPH2 was one of a small number of cytosolic proteins that form disulfide-bonded aggregates. The propensity of TPH2 to misfold upon oxidation of its cysteine residues is responsible for its catalytic lability and may be related to loss of serotonin neuronal function in PD and the emergence of non-motor (psychiatric) symptoms." @default.
• W1564508078 created "2016-06-24" @default.
• W1564508078 creator A5029519503 @default.
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• W1564508078 creator A5083492747 @default.
• W1564508078 creator A5091103743 @default.
• W1564508078 date "2010-12-13" @default.
• W1564508078 modified "2023-09-27" @default.
• W1564508078 title "Tryptophan hydroxylase 2 aggregates through disulfide cross-linking upon oxidation: possible link to serotonin deficits and non-motor symptoms in Parkinson’s disease" @default.
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• W1564508078 doi "https://doi.org/10.1111/j.1471-4159.2010.07123.x" @default.
• W1564508078 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3019244" @default.
• W1564508078 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21105877" @default.
• W1564508078 hasPublicationYear "2010" @default.
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