title: Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions.
abstract: BACKGROUND
  Demyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction. However, oxidative stress-induced mitochondrial dysfunction likely alters glucose metabolism and consequently impairs neuronal function in MS. Imaging and pathological studies indicate that glucose metabolism is altered in MS, although the underlying mechanisms and its role in neurodegeneration remain elusive. We investigated expression patterns of key enzymes involved in glycolysis, tricarboxylic acid (TCA) cycle and lactate metabolism in well-characterized MS tissue to establish which regulators of glucose metabolism are involved in MS and to identify underlying mechanisms.
  
  
  RESULTS
  Expression levels of glycolytic enzymes were increased in active and inactive MS lesions, whereas expression levels of enzymes involved in the TCA cycle were upregulated in active MS lesions, but not in inactive MS lesions. We observed reduced expression and production capacity of mitochondrial α-ketoglutarate dehydrogenase (αKGDH) in demyelinated axons, which correlated with signs of axonal dysfunction. In inactive lesions, increased expression of lactate-producing enzymes was observed in astrocytes, whereas lactate-catabolising enzymes were mainly detected in axons. Our results demonstrate that the expression of various enzymes involved in glucose metabolism is increased in both astrocytes and axons in active MS lesions. In inactive MS lesions, we provide evidence that astrocytes undergo a glycolytic shift resulting in enhanced astrocyte-axon lactate shuttling, which may be pivotal for the survival of demyelinated axons.
  
  
  CONCLUSIONS
  In conclusion, we show that key enzymes involved in energy metabolism are differentially expressed in active and inactive MS lesions. Our findings imply that, in addition to reduced oxidative phosphorylation activity, other bioenergetic pathways are affected as well, which may contribute to ongoing axonal degeneration in MS.
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Nijland
authors.affiliation: Department of Cell Biology & Histology, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Remco J
authors.initials: RJ
authors.lastname: Molenaar
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: van der Pol
authors.affiliation: Department of Pathology, VU University Medical Center, 1007MB, Amsterdam, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.affiliation: Department of Cell Biology & Histology, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: van Noorden
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. j.vanhorssen@vumc.nl.
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020122:tert-Butylhydroperoxide; D007770:L-Lactate Dehydrogenase; D007655:Ketoglutarate Dehydrogenase Complex; D005947:Glucose