Differential display reveals deteriorated mRNA levels of NADH3 (complex I) in cerebellum of patients with Down Syndrome
Although gene hunting has been carried out in Down Syndrome (DS) cells, information on expressional differences in DS brain is limited. We have recently described expressional differences in fetal DS brain but cannot assign these findings to “DS per” se or simply to “neurodegeneration”.
We therefore performed gene hunting in cerebellum of adult patients with DS and Alzheimer’s disease (AD) neuropathology, AD and controls. The gene hunting method used was differential display and pools of the individual groups were examined to rule out allelic differences.
Differential display revealed the absence of a band, identified by sequencing and gene bank work as matching the NADH3 gene (99.1% identity) in cerebellum of DS patients. Dot blots showed the presence of NADH3 signals in only two out of 7 DS patients.
We show at the transcriptional level that a mitochondrial enzyme, the complex I, NADH3, is significantly downregulated in DS cerebellum. This extends previous work on deficiencies of the electron transport chain in platelets of patients with DS.
KeywordsDown Syndrome Differential Display Down Syndrome Patient Expressional Difference NADH3 Gene
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Arnason U, Xu X, Gullberg A (1996) Comparison between the complete DNA sequences of homo and the common chimpanzee based on non-chimeric sequences. J Mol Evol 42: 145–152PubMedCrossRefGoogle Scholar
Benzi G, Moretti A (1995) Are reactive oxygen species involved in Alzheimer’s disease? Neurobiol Aging 16: 661–674PubMedCrossRefGoogle 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
Busciglio J, Yankner BA (1995) Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 378: 776–779PubMedCrossRefGoogle Scholar
Casserino DS, Bennett JP (1999) An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear Responses and cell death in neurodegeneration. Brain Res Rev 29: 1–25CrossRefGoogle Scholar
Chen H, Morris MA, Rossier C, Blouin JL, Antonarakis SE (1995) Cloning of the cDNA for the human ATP synthase OSCP subunit (ATP50) by exon trapping and mapping to chromosome 21q22.1-q22.2. Genomics 28: 470–476PubMedCrossRefGoogle Scholar
De Coo RFM, Buddiger P, Smeets HJM, van Oost BA (1997) Molecular cloning and characterization of the human mitochondrial NADH:oxidoreductase 10kDa gene (NDUFV3). Genomics 45: 434–437PubMedCrossRefGoogle Scholar
Epstein CJ (1992) Down Syndrome (Trisomy 21) In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw Hill, New York, pp 749–794Google Scholar
Gabuzda D, Busciglio J, Chen LB, Matsudiara P, Yankner B (1994) Inhibition of energy metabolism alters the processing of the amyloid precursor protein and indeuces a potentialoly amyloidogenic derivative. J Biol Chem 269: 13623–13628PubMedGoogle Scholar
Greber-Platzer S, Schatzmann-Turhani D, Wollenek G, Lubec G (1999) Evidence against the current hypothesis of “gene dosage effects” of trisomy 21: ets2, encoded on chromosome 21 is not overexpressed in hearts of patienjts with Down Syndrome. Biochem Biophys Res Commun 254: 395–399PubMedCrossRefGoogle Scholar
Hardmeier R, Hoeger H, Khoshsorur A, Lubec G (1997) Transcription and activity of superoxide dismutase, catalase and glutathione peroxidase following irradiation in radiation resistant and radiation sensitive mice. Proc Natl Acad Sci USA 94: 7572–7576PubMedCrossRefGoogle Scholar
Hayn M, Kremser K, Singewald N, Nemethova M, Lubec G (1996) Evidence against the involvement of active oxygen species in the pathogenesis of Down Syndrome and Alzheimer Disease. Life Sci 59: 537–544PubMedCrossRefGoogle Scholar
Kitzmueller E, Labudova O, Cairns N, Lubec G (1999) Differences in gene expression in fetal Down Syndrome brain. J Neural Transm (this volume)Google Scholar
Labudova O, Krapfenbauer K, Moenkemann H, Rink H, Kitzmüller E, Cairns N, Lubec G (1998) Decreased transcription factor junD in brains of patients with Down Syndrome. Neurosci Lett 252: 159–162PubMedCrossRefGoogle Scholar
Labudova O, Kitzmueller E, Rink H, Cairns N, Lubec G (1999) Gene expression in fetal Down Syndrome brain as revealed by subtractive hybridization. J Neural Transm (this volume)Google Scholar
Labudova O, Kitzmüller E, Rink H, Cairns N, Lubec G (1999) Increased phosphoglycer-ate kinase in brains of patients with Down’s syndrome but not with Alzheimer’s disease. Clin Sci 96: 279–285PubMedCrossRefGoogle Scholar
Markesberry WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23: 134–147CrossRefGoogle Scholar
Mirra SS, Heyman A, McKeel D, Sumi S, Crain BJ (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). II. Standardization of the neuropatho-logical assessment of Alzheimer’s disease. Neurology 41: 479–486PubMedCrossRefGoogle Scholar
Parker WD, Parks JK, Filley CM, Kleinschmidt-DeMasters (1994) Electron transport defects in Alzheimer’s disease braqin. Neurology 44: 1090–1096PubMedCrossRefGoogle Scholar
Prince J, Jia S, Bave U, Anneren G, Oreland L (1994) Mitochondrial enzyme deficiencies in Down’s syndrome. J Neural Transm [PD-Sect] 8: 171–181CrossRefGoogle Scholar
Seidl R, Schuller E, Cairns N, Lubec G (1997) Evidence against increased glycoxidation in Alzheimer’s disease. Neurosci Lett 232: 49–52PubMedCrossRefGoogle Scholar
Seidl R, Greber S, Schuller E, Bernert G, Cairns N, Lubec G (1997) Evidence against increased oxidative DANN-damage in Down Syndrome. Neurosci Lett 235:137–140PubMedCrossRefGoogle Scholar
Smith TS, Bennett Jr JP (1997) Mitochondrial toxins in neurodegenerative diseases. I. In vivo brain hydroxyl radical production during systemic MPTP treatment or following microdialysis infusion of methylpyridinium or azide ions. Brain Res 765: 183–186PubMedCrossRefGoogle Scholar
Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett Jr JP, Davis RE, Parker Jr WD (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49: 918–925PubMedCrossRefGoogle Scholar
Tierney MC, Fisher RH, Lewis AJ, Torzitto ML, Snow WG, Reid DW, Nieuwstraten P, Van Rooijen LAA, Derks HJMG, Van Wijk R, Bischop A (1988) The NINCDA-ADRDA work group criteria for the clinical diagnosis of probable Alzheimer’s disease. Neurology 38: 359–364PubMedCrossRefGoogle Scholar
Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17: 278–282PubMedCrossRefGoogle Scholar
© Springer-Verlag Wien 1999