Mutations in the IDO2 gene and DNA methylations in genes in the NAD/NADP synthesis pathway in ME

Results shown at the NIH ME/CFS conference indicate that all of the 20 of the severely ill ME patients had damaging mutations in their indolamine 2,3-dioxygenase 2 (IDO2) gene (1,2).

The enzymes IDO1 and IDO2 catalyze the conversion of tryptophan to N-formyl-kynurenine. This is the first step in the kynurenine pathway and in the de novo pathway of biosynthesis of  NAD+  and  NADP+  (3).

Use link below to see "Biosynthesis of NAD(P)+ in mammalian cells" (3):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737637/figure/f2/

NAD+ is synthesized by three pathways: 

• the de novo pathway
• the Preiss–Handler pathway
• the salvage pathway 

All of the enzymes in these three pathways are thoroughly described in reference 3. Some of these enzymes show up in ME research:

NAMPT = nicotinamide phosphoribosyltransferase. NAMPT is an enzyme in the salvage pathway.
NADSYN1 = NAD synthetase 1. NADSYN1 is an enzyme in the Preiss–Handler pathway.
QPRT = quinolinate phosphoribosyltransferase. QPRT is an enzyme the de novo pathway.
NADK = NAD kinase. NADK catalyzes the transfer of a phosphate group from ATP to NAD to generate NADP.

NAMPT gene expression was increased in whole blood from adolescent ME/CFS patients (adjusted p-value = 0,0621) (4).

NAMPT gene expression was increased in peripheral blood mononuclear cells (PBMC) from ME patients (5).


DNA methylations of genes in PBMC from ME patients:

• NADSYN1 hypermethylated (gene probe cg 03146219) (6)
• NADSYN1 hypomethylated (5'UTR) (7)

• QPRT differentially methylated (1stExon) in ME patient subtypes (8)

• NADK hypermethylated (gen probe cg00343906) (6)
• NADK hypermethyltated (body) (9)
• NADK differentially methylated (body) in ME patient subtypes (8)
• NADK hypometylated (TSS1500) (7)

Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections

The tryptophan-kynurenine-nicotinamide adenine dinucleotide (oxidized; NAD+) pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in central nervous system (CNS) infections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers (10).

The Trp-Kyn-NAD+ pathway is activated in CNS infections and provides highly accurate CSF biomarkers, particularly when combined with standard CSF indices of neuroinflammation (10).

The ME metabolic trap hypothesis predicts dysregulated Trp-Kyn- pathway in immune cells from ME patients (11).


Is the Trp-Kyn-NAD+ pathway dysregulated in the cerebrospinal fluid from ME patients?

References

1) National Institute of Health ME/CFS konference april 2019,
del 1: https://videocast.nih.gov/summary.asp?live=31636&bhcp=1
del 2: https://videocast.nih.gov/summary.asp?Live=31640&bhcp=1

2)  Health Rising,   NIH ME/CFS Conferencen, april 2019:
https://www.healthrising.org/blog/2019/04/10/nih-accelerating-chronic-fatigue-exhaustion-inflammation/

3) Xiao et al: NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism Antioxid Redox Signal. 2018 Jan 20;28(3):251-272. doi: 10.1089/ars.2017.7216. Epub 2017 Jul 28.

https://www.ncbi.nlm.nih.gov/pubmed/28648096

4) Nguyen et al: Whole blood gene expression in adolescent CFS: an exploratory crosssectional study suggesting altered B cell differentiation and survival. J Transl Med. 2017,15,102.  https://www.ncbi.nlm.nih.gov/pubmed/28494812

5) 12) Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.
https://www.ncbi.nlm.nih.gov/pubmed/30791746

6) 4) de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104757

7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns. Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

8) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

9) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230

10) Sühs et al: Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections J Infect Dis. 2019 Jun 5;220(1):127-138. doi: 10.1093/infdis/jiz048.
https://www.ncbi.nlm.nih.gov/pubmed/30721966

11) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phairhttps://www.youtube.com/watch?v=Quh-77gvw4Q