Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
This plot shows the levels of quinolinic acid measured in trisomy 21 (right) compared to typicals (left).
In this study, our scientists measured 91 metabolites using mass spectrometry and compared the levels of each metabolite in people with Down syndrome to those without. They found 29 metabolites whose levels were significantly altered in people with Down syndrome. The metabolite that was most significantly elevated was quinolinic acid (see figure to the right), which can be neurotoxic and is associated with diverse neurological disorders (e.g. Alzheimer’s disease, Huntington’s disease, multiple sclerosis, etc.) Quinolinic acid is produced as a byproduct of the kynurenine metabolic pathway, a pathway whose job is to break down the essential amino acid tryptophan to produce other molecules needed by the body. Everyone produces some quinolinic acid, but on average, people with Down syndrome produced much more.
Our scientists also found that a particular enzyme in the kynurenine pathway, called IDO1, is upregulated in the white blood cells from people with Down syndrome. The IDO1 enzyme helps drive the production of quinolinic acid and is induced by interferon signaling, which we previously showed is consistently activated in people with Down syndrome. Lastly, to determine why people with Down syndrome have dysregulation of the kynurenine pathway, our scientists did two very important experiments:
They used a cell culture model to show that the expression of two interferon receptors, which are located on chromosome 21, is necessary for activation of the kynurenine pathway.
They used mouse models of Down syndrome to show that the kynurenine pathway is only elevated in mice who have three copies of certain interferon receptors, as in people with Down syndrome.
This research suggests that activation of the kynurenine pathway may contribute to the spectrum of neurological conditions experienced by many people with Down syndrome, including early onset of Alzheimer’s disease, and seizures, autism, and depression, via neurotoxic quinolinic acid. This research also provides evidence that the root cause of the activation of the kynurenine pathway in people with Down syndrome is the triplication of the interferon receptors located on chromosome 21, which lead to an increase in interferon signaling.
Check out the full publication on PubMed.
Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors. Rani K. Powers, Rachel Culp-Hill, Michael P. Ludwig, Keith P. Smith, Katherine A. Waugh, Ross Minter, Kathryn D. Tuttle, Hannah C. Lewis, Angela L. Rachubinski, Ross E. Granrath, María Carmona-Iragui, Rebecca B. Wilkerson, Darcy E. Kahn, Molishree Joshi, Alberto Lleó, Rafael Blesa, Juan Fortea, Angelo D’Alessandro, James C. Costello, Kelly D. Sullivan, and Joaquin M. Espinosa. Nat Commun. 2019; 10: 4766. PMID: 31628327. PMCID: PMC6800452.