nAChR, agrin, rapsyn and ME

Nicotinic acatylcholine receptors (nAChRs) are suspected to be involved in the ME pathomechanism (1).

ME patients have dysregulated lipid metabolism (2). This could have an impact on lipid rafts?

Lipid rafts serve as signaling platforms for nAChRs clustering. The clustering is induced by the heparan sulphate proteoglyan, agrin. The nAChRs are anchored into the lipid rafts by rapsyn (3).

A proteomic study on cerebrospinal fluid from ME patients has shown an upregulation of the arin precursor and of the heparan sulfate proteoglyan core protein precursor (4).

The gene RAPSN (protein: rapsyn) has been found epigenetic changed (hypermethylated) in ME (5).

References:

1. Griffith University. https://www.griffith.edu.au/health/national-centre-neuroimmunology-emerging-diseases
2. Naviaux et al: Metabolic features of CFS. www.pnas.org/cgi/doi/10.1073/pnas.1607571113
3. Allen et al: Lipid raft microdomains and neurotransmitter signalling. Nature Reviews, feb 2007, vol 8.
4. Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue 
5. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757

Sidder sjælen i blodet?

I Danmark kaldes Myalgisk Encephalomyelitis / Chronic Fatigue Syndrome ME/CFS) for en funktionel lidelse, som beskrives som en sygdom mellem krop og sjæl. Der anbefales intens behandling med kognitiv terapi, hvilket må formodes at være rettet mod sjælen (1).

I Norge er kræftlægerne Fluge og Mella i færd med at gennemføre et Rituximab – fase III – studie til behandling af ME/CFS (2).

Nu er Fluge, Mella og deres forsker-team aktuelle med et nyt studie, hvor der deltog 200 ME/CFS patienter og 102 raske kontrolpersoner. Analyse af ME/CFS patienternes metabolisme viste:

• En reduktion af aminosyrer, der anvendes til oxidativ metabolisme via trikarboxylsyrecyklus. Dette sås hovedsagelig hos de kvindelige patienter.
• Serum 3-metylhistidin, som er markør for endogen protein katabolisme, var signifikant øget hos mænd.
• En aminosyrer omsætning, der tydede på nedsat pyruvat dehydrogenase funktion.
• Øget mRNA ekspression af de inhibitoriske pyruvat dehydrogenase kinaser (PDK) 1, 2 og 4; sirtuin 4 og PPAR-delta. Dette fund forekom hos både mænd og kvinder.
• mRNA ekspression af PDK1 korrelerede med sygdomsgrad.
• Muskelceller in vitro der blev tilført serum fra ME/CFS patienter udviklede metaboliske tilpasninger i form af øget mitokondriel respiration og forhøjet laktat produktion ved forskellige test, der simulerede muskelbelastning. Dvs et respons der er i overenstemmelse med det kliniske sygdomsbillede af ME/CFS med utilstrækkelig ATP dannelse ved oxidativ fosforylering og forøget laktat dannelse ved belastning (3).

Det er ganske interessant, at blod fra ME/CFS patienter kan ændre metabolismen i muskelceller i et reagensglas. Det får mig til at stille spørgsmålet: ”Sidder sjælen i blodet?”

Mediedækning af forskningen:

Fluge og Mellas ME-forskning var i Norges TV2 nyheder d. 4/1.

https://www.youtube.com/watch?v=ZvWFwj-N9dk  (3.36 min)

Der var også et indslag i norsk TV2 d. 5/1 med Fag-direktør Per Magnus fra Folkehelse-instituttet.
https://www.youtube.com/watch?v=XYziEAz3FSk (1.19 min)

Og Hanne Thurmer, en af forskerne bag Rituximab-studiet, var i norsk radio på NRK Telemark d. 5/1.
https://radio.nrk.no/serie/distriktsprogram-telemark/DKTE02000417/05-01-2017#t=1h5m54s

Jyllandsposten.
http://jyllands-posten.dk/international/europa/ECE9278647/nordmand-i-hi-paa-11-aar-har-aldrig-set-en-iphone-eller-facebook/

Referencer:

1. Funktionel lidelser. Klinisk Vejledning for almen praksis. Dansk Selskab for Almen Medicin, 2013
2. ”B-lymphocyte depletion using rituximab in chronic fatigue syndrome/myalgic encephalopathy (CFS/ME). A randomized phase-III study. (RituxME)” Clinical Trials.gov Identifier: NCT02229942 https://clinicaltrials.gov/ct2/NCT02229942
3. Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276

Pyruvate and ME/POTS

Fluge, Mella et al. have shown that ME is associated with defective oxidative metabolism - most likely involving impaired pyruvate dehydrogenase function (1).

Expression of the protein mitochondrial pyruvate carrier 2 (MCC2) has been found downregulated in ME (2)

The gene similar to pyruvate kinase-isozymes M1/M2 (PKM2) has been found epigenetic changed (hypermethylated) in ME (3).

Immunoreactive proteins against IgGs from POTS patients (4, 5):

• ODPB, pyruvate dehydrogenase E1 component subunit beta.
• KPYM, pyruvate kinase isoenzyme M1.
• PDHX, pyruvate dehydrogenase protein X component.
• PKM2, pyruvate kinase isozymes M1/M2

References:

1.  Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
2. Ciregia et al.
   Translational Psychiatry (2016), 6, e904
   doi:10.1038/tp.2016.184
3. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757
4. Wang et al: Autoimmunoreactive IgGs from patients with POTS. Prot. Clin. Appl. 2012, 6, 1-11.
5. Wang et al: Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with POTS. doi: 10.1016/j.trsl.2013.03.002

ALDH4A1 and ME

Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH4A1 gene (aldehyde dehydrogenase 4 family, member A1). This enzyme is a mitochondrial matrix NAD-dependent dehydrogenase that catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate. Deficiency of this enzyme is associated with type II hyperprolinemia, an autosomal recessive disorder characterized by accumulation of delta-1-pyrroline-5-carboxylate (P5C) and proline. (1).

Pyrroline-5-carboxylic acid is increased in ME patients (2).

The gene ALDH4A1 has been found epigenetic changed (hypermethylated) in ME (3).

Expression of the proteins P5C-dehyrogenase and P5C-synthase have been found upregulated in ME (4).

P5C-dehydrogenase has been found to be an immunoreactive protein against IgGs from POTS-patients (5).

References:

1. Wikipedia: Aldehyde dehydrogenase 4 family, member A1
2. Naviaux et al: Metabolic features of CFS. www.pnas.org/cgi/doi/10.1073/pnas.1607571113
3. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e10475
4. Ciregia et al.
   Translational Psychiatry (2016), 6, e904
   doi:10.1038/tp.2016.184
5. Wang et al: Autoimmunoreactive IgGs from patients with POTS. Prot. Clin. Appl. 2012, 6, 1-11.

ACAD8 and ME

Fluge, Mella et al. have shown that ME is associated with defective oxidative metabolism - most likely involving impaired pyruvate dehydrogenase function - leading to increased utilization  of ketogenic amino acids to fuel the TCA-cycle (1).

A proteomic study on cerebrospinal fluid from ME/CFS patients has shown an upregulation of the pathway "valine, leucine and isoleucine degradation" (table S6 in ref 2).

The gene acyl-CoA.dehydrogenase family member 8 (ACAD8) has been found epigenetic changed (hypermethylated) in ME (3).

ACAD8 is an isobutyryl-CoA dehydrogenase that functions in the catabolism of branched-chain amino acids including valine, and shows high reactivity toward isobutyryl-CoA. ACAD8 is responsible for the third step in the breakdown of valine and converts isobutyryl-CoA into methylacrylyl-CoA.

References:

1. Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
2. Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue 2
3. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757
4. Wikipedia: ACAD8

HMGCL and ME

Fluge, Mella et al. have shown that ME is associated with defective oxidative metabolism - most likely involving impaired pyruvate dehydrogenase function - leading to increased utilization  of ketogenic amino acids (1).

Hydroxymethyl - methylglutaryl - CoA-lyase (HMGCL) is a key enzyme in ketone body formation.

Expression of the protein HMGCL has been found upregulated in ME (2).

The gene HMGCL has been found epigenetic changed (hypermethylated) in ME (3).

Reference:

1.  Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
2. Ciregia et al.
   Translational Psychiatry (2016), 6, e904
   doi:10.1038/tp.2016.184
3. Vega et al. DNA methylation Modifications associated with CFS. Plos One, aug 2014, vol 9, Issue 8, e104757