Carbohydrate handling enzymes in fetal Down Syndrome brain
Impaired glucose metabolism in adult Down Syndrome (DS) has been well-documented in vivo and information on the underlying biochemical defect i.e. aberrant glucose handling enzymes is already available. Nothing is known on carbohydrate handling, however, in early life of DS patients, when no secondary phenomena as e.g. Alzheimer-like neuropathology occur in the brain yet.
We therefore determined a series of key enzymes of carbohydrate metabolism in fetal control and DS brain during the early second trimenon. We used two-dimensional electrophoresis with subsequent MALDI characterization and specific software for quantification of protein spots.
We observed comparable levels of phosphoglycerate mutase, phospho-glycerate kinase 1; fructose-biphosphate aldolase A, fructose bisphosphate aldolase C; ribose-phosphate pyrophosphokinase 1; D-phosphoglycerate dehydrogenase, 6-phosphogluconolactonase; aflatoxin B1 aldehyde reductase 1, aldose reductase; inosine-5’-monophosphate dehydrogenase 2; galactokinase, in brain of fetal controls and DS.
We conclude that our biochemical findings point to the fact that DS patients start early life with unchanged glucose handling, pentose phosphate shunt, glycolysis, sugar aldehyde, guanine nucleotide- and ribonucleoside formation and galactose metabolism.
KeywordsDown Syndrome Aldose Reductase Phosphoglycerate Kinase Cerebral Glucose Metabolism Fructose Bisphosphate Aldolase
Anneren KG, Korenberg JR, Epstein CJ (1987) Phosphofructokinase activity in fibroblasts aneuploid for chromosome 21. Hum Genet 76: 63–65PubMedCrossRefGoogle Scholar
Berndt P, Hobohm U, Langen H (1999) Reliable automatic protein identification from matrix-assisted laser desorption mass spectrometric peptide fingerprints. Electrophoresis 20: 3521–3526PubMedCrossRefGoogle Scholar
Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254PubMedCrossRefGoogle Scholar
Buono P, Paolella G, Mancini FP, Izzo P, Salvatore F (1988) The complete nucleotide sequence of the gene coding for the human aldolase C. Nucl Acids Res 16: 4733–4737PubMedCrossRefGoogle Scholar
Burger PC, Vogel FS (1973) The development of pathologic changes of Alzheimer’s disease and senile dementia in patients with Down’s syndrome. Am J Pathol 73: 457–476PubMedGoogle Scholar
Collard F, Collet JF, Gerin I, Veiga da Cunha M, Van Schaffingen E (1999) Identification of the cDNA encoding human 6-phosphogluconolactonase, the enzyme catalysing the second step of the pentose phosphate pathway. FEBS Lett 459: 223–226PubMedCrossRefGoogle Scholar
Collart FR, Hubermann E (1988) Cloning and sequencing analysis of the human and Chinese hamster inosine-5´-monophosphate dehydrogenase cDNAs. J Biol Chem 263: 15769–15772PubMedGoogle Scholar
Dani A, Pietrini P, Furey M, Mcintosh CL, Horwitz B, Freo U, Alexander GE, Schapiro MB (1996) Brain cognition and metabolism of Down syndrome adults in association with development of dementia. Neuroreport 7: 2933–2936PubMedCrossRefGoogle Scholar
Epstein CJ (1992) Down Syndrome (Trisomy 21). In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw Hill, New York, pp 749–794Google Scholar
Fountoulakis M, Langen H (1997) Identification of proteins by matrix-assisted laser desorption ionization mass spectrometry following in-gel digestion in low-salt, nonvolatile buffer and simplified peptide recovery. Anal Biochem 250: 153–156PubMedCrossRefGoogle Scholar
Haxby JV, Duara R, Grady CL, Cutler NR, Rapoport SI (1985) Relations between neuropsychological and cerebral metabolic asymmetries in early Alzheimer’s disease. J Cereb Blood Flow Metab 5: 193–200PubMedCrossRefGoogle Scholar
Hsia DY-Y, Justice P, Smith GF, Dowben RF (1971) Down’s syndrome. A critical review of the biochemical and immunological data. Am J Dis Child 121: 153–171PubMedGoogle Scholar
Ireland LS, Harrison DJ, Neal GE, Hayes JD (1998) Molecular cloning, expression and catalytic activity of a human AKR7 member of the aldo-keto-reductase superfamily; evidence that the major 2-carboxybenzaldehyde reductase from human liver is a homologue of rat aflatoxin Bl-aldehyde reductase. Biochem J 332: 21–34PubMedGoogle Scholar
Izzo P, Costanzo P, Lupo A, Rippa E, Paolella G, Salvatore F (1987) A new human species of aldolase A mRNA from fibroblasts. Eur J Biochem 164: 9–13PubMedCrossRefGoogle Scholar
Labudova O, Kitzmueller E, Rink H, Cairns N, Lubec G (1999a) Increased phosphoglycerate kinase in the brains of patients with Down Syndrome but not with Alzheimer’s disease. Clin Sci 96: 279–285PubMedCrossRefGoogle Scholar
Labudova O, Cairns N, Kitzmueller E, Lubec G (1999) Impaired brain glucose metabolism in patients with Down Syndrome. J Neural Transm [Suppl] 57: 247–256Google Scholar
Langen H, Roeder D, Juranville J-F, Fountoulakis M (1997) Effect of the protein application mode and the acrylamide concentration on the resolution of protein spots separated by two-dimensional gel electrophoresis. Electrophoresis 18: 2085–2090PubMedCrossRefGoogle Scholar
Lubec G, Labudova O, Cairns N, Fountoulakis M (1999) Increased glyceraldehyde-3-phosphate dehydrogenase levels in brain of patients with Down Syndrome. Neurosci Lett 260: 141–145PubMedCrossRefGoogle Scholar
Lubec G, Labudova O, Cairns N, Berndt P, Langen H, Fountoulakis M (1999) Reduced aldehyde dehydrogenase in brain of patients with Down Syndrome. J Neural Transm [Suppl] 57: 21–40Google Scholar
Pietrini P, Dani A, Furey ML, Alexander GE, Freo U, Grady CL, Mentis MJ, Mangot D, Simon EW, Horwitz B, Haxby JV, Schapiro MB (1997) Low glucose metabolism during brain stimulation in older Down’s Syndrome subjects at risk for Alzheimer’s disease prior to dementia. Am J Psychiatry 154: 1063–1069PubMedGoogle Scholar
Roessler BJ, Palella TD, Heidler S, Becker MA (1991) Identification of distinct PRPS1 mutations in two patients with X-linked phosphoribosylpyrophosphate synthase superactivity. Clin Res 39: 267A–276AGoogle Scholar
Schapiro MB, Grady CL, Haxby JV (1992) Nature of mental retardation and dementia in Down’s syndrome: study with PET, CT, and neuropsychology. Neurobiol Aging 13: 723–734PubMedCrossRefGoogle Scholar
Van Keuren M, Drabkin H, Hart I, Patterson D, Vora S (1985) Regional mapping of liver type 6 phosphofructokinase to 21q22.3. Am J Hum Genet 37: A20–26Google Scholar
Vora S, Franke U (1981) Assignment of the human gene for liver-type 6-phosphofruc- tokinase isoenzyme (PFK-L) to chromosome 21 by using somatic cell hybrids and monoclonal anti-L-antibody. Proc Natl Acad Sci USA 78: 3738–3742PubMedCrossRefGoogle Scholar
Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and demential of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17: 278–282PubMedCrossRefGoogle Scholar
© Springer-Verlag/Wien 2001