Parkinson’s disease

Tryptophan dioxygenase is a promising new drug target for neurodegenerative disease, including Parkinson’s disease. NTRC has developed a proprietary assay technology for high-throughput screening of tryptophan catabolizing enzymes.

Tryptophan is an essential amino acid that is used for protein synthesis and the production of neurotransmitters that regulate behaviour, such as serotonin and melatonin. Aberrant tryptophan catabolism has been implicated in a number of diseases, including cancer, and neurodegenerative diseases. The first and rate-limiting enzymes in the degradation of tryptophan are indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). Both enzymes have a different tissue distribution and different physiological roles. Whereas IDO1 is broadly expressed, and acts locally, TDO is constitutively expressed at high levels in the liver, where it regulates systemic tryptophan levels. Despite catalysing the same reaction, the two enzymes do have little structural similarity. There is increasing evidence that aberrant TDO activity contributes to neurodegenerative disease. Patients with Alzheimer’s disease have low levels of serum tryptophan and high levels of serum kynurenine, and these changes correlate with the level of cognitive decline. TDO was found to be overexpressed in brain tissue of Alheimer’s disease patients. Brain levels of quinolinic acid, kynurenic acid and 3-hydroxykynurenine have been reported to be elevated in early phases of Huntington’s disease, in line with findings in mouse models. Recently, TDO was identified as a metabolic regulator of age-related alpha-synuclein toxicity in a Caenorhabditis elegans model [1]. Depletion of TDO suppressed toxicity of amyloid-β and poly-glutamine, and increased lifespan. The same effect could be obtained by addition of dietary L-tryptophan. These studies support the idea that restoring the balance in tryptophan metabolism may provide therapeutic benefit in patients with neurodegenerative disease.
NTRC scientist have developed a new and innovative screening assay for TDO, NFK Green™, and have applied this assay for ultra-high throughput screening at the Pivot Park Screening Centre.

[1] Van der Goot AT, Zhu W, Vázquez-Manrique RP, Seinstra RI, Dettmer K, Michels H, Farina F, Krijnen J, Melki R,  Buijsman RC, Silva MR, Thijssen KL, Kema I, Neri C, Oefner PJ, Nollen EAA, Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation (2012) Proc Natl Acad Sci U S A, 109(37), 14912-7.

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Parkinson's disease