COG3, LPAAT3, ERGIC and ME

What is going on in the endoplasmic reticulum (ER) and the golgi complex in ME patients?

The gene COG3, component of oligomeric golgi complex 3, is hypomethylated in ME patients (1). The COG is required for normal golgi morphology and localization. Defects in the COG complex result in multiple deficiencies in protein glycosylation (2).

Some ME patients have SNP in the gene AGPAT3, also known as LPAAT3, lysophosphatidic acid acyltransferase 3 (3). LPAAT3 regulates golgi complex structure and function (4).

The gene ERGIC1, ER-golgi intermediate compartment 1, is hypermethylated (5). ERGIC1 is a cycling membrane protein which interacts with other members of this protein family to increase their turnover (2).

The ERGIC53 precursor is up-regulated in the cerebrospinal fluid, CFS:9 and normal value:1 (6). ERGIC53 is also known as LMAN1, lectin mannose binding 1. The protein cycles between ER and golgi, functioning as a cargo receptor for glycoprotein transport (2). LPAAT3 affects the recycling of ERGIC53 (4).

Ceramides are downregulated in the plasma from ME patients (7). The spingosine backbone from short chain ceramides is used (recycled) to make long chain ceramides. This process takes place in the golgi complex. The mycotoxin brefeldin A is used in golgi research, because it causes disassembly of the golgi complex. Research has shown that the salvage of the sphingosine backbone of short-chain ceramide to form long-chain ceramide was attenuated by brefeldin A (8).

There are many more ER/golgi genes and proteins, which are changed in ME patients compared to normal controls in references 5 and 6. Are the changes involved in cause or consequence of the ME pathomechanism?

References:

1. Brenu et al: Methylation profile of CD4+ T cells in CFS/ME. J. Clin Cell Immunol 5, 228
2. www.ncbi.nlm.nih.gov/gene
3. Schlauch et al: Genome-wide association analysis identifies genetic variations in subjects with ME/CTS. 2016.doi.10.1038/tp.2015.208
4. Schmidt and Brown: Lysophosphatic acid acyltransferase 3 regulates golgi complex structure and function. J. Cell Biol. Vol. 186, No2, 2009
5. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757
6. Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue
7. Naviaux et al: Metabolic features of CFS. www.pnas.org/cgi/doi/10.1073/pnas.1607571113
8. Kitatani: The sphingolipid salvage pathway inceramide metabolism and signaling. Cell Signal 2008 Jun 20, 6.

Choline, ME og POTS

Choline ( dansk: kolin) er et næringsstof, som vi indtager gennem kosten. Choline er byggesten for:

• phosphatidylcholine, som er et lipid i cellemembranen
• neurotransmitteren acetylcholine
• betaine, som er methylgruppe-donor og en vigtig osmolyt

Opdagelse af choline

Tre typer transportproteiner sørger for optagelse af choline:

• organic cation transporters
• high affinity choline transporters, som er tæt associeret med syntese af acetylcholine i neuronerne
• solute carriers, SLC44A1, SLC44A2 og SLC44A3

Syntese af phosphatidylcholine

Choline omdannes til phosphatidylcholine (PC) via tre enzymer i tre trin, som hedder CDP-choline eller Kennedy stivejen:

• choline omdannes til phospho-choline af choline kinase
• phospho-choline omdannes til cytidinediphosphocholine (CDP-choline) af phosphocholinecytidyltransferase (PCYT1A)
• CDP-choline omdannes til PC af cholinephosphotransferase (1)

ME forskning

Følgende gener er fundet epigenetisk ændrede hos ME patienter (2,3):

• PCYT1A, hypomethyleret
• SLC44A1, hypermethyleret
• SLC44A2, hypermethyleret
• SLC44A3, hypermethyleret

Metaboliterne CDP-choline og choline phosphate(1-) er fundet nedregulerede i plasma fra ME-patienter (4).

POTS forskning

Undersøgelse af celler fra en enkelt POTS-patient viste, at patienten havde nedsat mRNA ekspression af SLC44A1 og choline optagelsen var reduceret med 60%. Lipidsammensætning i lipid rafts var ændret, hvilket påvirkede membran-permabilitet og funktion. Samtidig blev der påvist mitokondrie dysfunktion (5).

Referencer:

1. Fagone og Jackowski: Phosphatidylcholine and the CDP-Choline Cycle. Biochim Biophys Acto. 2013 March, 1831, 3, 523-532.
2. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757
3. Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11
4. Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371
5. Schenkel et al: Mechanism of choline deficiency and membrane alteration in POTS primary skin fibroblasts. FASEB Journal, April 2015, Vol 29.