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[en] There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin-proteasome system, play an important role in the pathogenesis of Parkinson's disease. We now show that the corresponding pathways of these two systems are linked at the transcriptomic level in Parkinsonian substantia nigra. We examined gene expression in medial and lateral substantia nigra (SN) as well as in frontal cortex using whole genome DNA oligonucleotide microarrays. In this study, we use a hypothesis-driven approach in analysing microarray data to describe the expression of mitochondrial and ubiquitin-proteasomal system (UPS) genes in Parkinson's disease (PD). Although a number of genes showed up-regulation, we found an overall decrease in expression affecting the majority of mitochondrial and UPS sequences. The down-regulated genes include genes that encode subunits of complex I and the Parkinson's-disease-linked UCHL1. The observed changes in expression were very similar for both medial and lateral SN and also affected the PD cerebral cortex. As revealed by "gene shaving" clustering analysis, there was a very significant correlation between the transcriptomic profiles of both systems including in control brains. Therefore, the mitochondria and the proteasome form a higher-order gene regulatory network that is severely perturbed in Parkinson's disease. Our quantitative results also suggest that Parkinson's disease is a disease of more than one cell class, i.e. that it goes beyond the catecholaminergic neuron and involves glia as well.
Disciplines :
Neurology
Author, co-author :
Duke, D. C.; Imperial College London > Department of Neuropathology
Moran, L. B.; Imperial College London > Department of Neuropathology
Kalaitzakis, M. E.; Imperial College London > Department of Neuropathology
Deprez, Manuel ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Dexter, D. T.; Imperial College London > Department of Cellular and Molecular Neuroscience
Pearce, R. K. B.; Imperial College London > Department of Neuropathology
Graeber, M. B.; Imperial College London > Department of Neuropathology
Language :
English
Title :
Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson's disease.
Publication date :
2006
Journal title :
Neurogenetics
ISSN :
1364-6745
eISSN :
1364-6753
Publisher :
Springer Verlag, New York, United States - New York
Volume :
7
Issue :
3
Pages :
139-48
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
UK Parkinson’s Disease Society Tissue Bank at Imperial College
Teravainen H, Forgach L, Hietanen M, Schulzer M, Schoenberg B, Calne DB (1986) The age of onset of Parkinson's disease: etiological implications. Can J Neurol Sci 13:317-319
Forno LS (1986) Lewy bodies. N Engl J Med 314:122
Graeber MB, Dexter D, Pearce RK, Reynolds R (2003) Parkinson's disease: an update. Neuropathol Appl Neurobiol 29:514-515
Gibb WR, Fearnley JM, Lees AJ (1990) The anatomy and pigmentation of the human substantia nigra in relation to selective neuronal vulnerability. Adv Neurol 53:31-34
Gibb WR (1991) Neuropathology of the substantia nigra. Eur Neurol 31(Suppl 1):48-59
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256-259
Zhang L, Shimoji M, Thomas B, Moore DJ, Yu SW, Marupudi NI, Torp R, Torgner IA, Ottersen OP, Dawson TM, Dawson VL (2005) Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 14:2063-2073
Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304:1158-1160
Grasbon-Frodl EM, Kosel S, Sprinzl M, von Eitzen U, Mehraein P, Graeber MB (1999) Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease. Neurogenetics 2:121-127
Kosel S, Grasbon-Frodl EM, Mautsch U, Egensperger R, von Eitzen U, Frishman D, Hofmann S, Gerbitz KD, Mehraein P, Graeber MB (1998) Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease. Neurogenetics 1:197-204
Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605-608
Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson's disease. Nature 395:451-452
Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1:126914
Mizuno Y, Yoshino H, Ikebe S, Hattori N, Kobayashi T, Shimoda-Matsubayashi S, Matsumine H, Kondo T (1998) Mitochondrial dysfunction in Parkinson's disease. Ann Neurol 44:S99-S109
Janetzky B, Hauck S, Youdim MB, Riederer P, Jellinger K, Pantucek F, Zochling R, Boissl KW, Reichmann H (1994) Unaltered aconitase activity, but decreased complex I activity in substantia nigra pars compacta of patients with Parkinson's disease. Neurosci Lett 169:126-128
McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW (2003) Altered proteasomal function in sporadic Parkinson's disease. Exp Neurol 179:38-46
Kolata G (1983) Monkey model of Parkinson's disease. Science 220:705
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3:1301-1306
Rideout HJ, Larsen KE, Sulzer D, Stefanis L (2001) Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells. J Neurochem 78:899-908
McNaught KS, Bjorklund LM, Belizaire R, Isacson O, Jenner P, Olanow CW (2002) Proteasome inhibition causes nigral degeneration with inclusion bodies in rats. Neuroreport 13:1437-1441
Moran LB, Duke DC, Deprez M, Dexter DT, Pearce RK, Graeber MB (2006) Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson's disease. Neurogenetics (In press)
Rango M, Bonifati C, Bresolin N (2006) Parkinson's disease and brain mitochondrial dysfunction: a functional phosphorus magnetic resonance spectroscopy study. J Cereb Blood Flow Metab 26:283-290
Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM (2005) A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain 128:2665-2674
Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, Torizuka T (2005) Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann Neurol 57:168-175
van Muiswinkel FL, de Vos RA, Bol JG, Andringa G, Jansen Steur EN, Ross D, Siegel D, Drukarch B (2004) Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol Aging 25:1253-1262
Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alphasynucleinpositive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson's disease brains. Acta Neuropathol (Berl) 99:14-20
Wakabayashi K, Mori F, Oyama Y, Kurihara A, Kamada M, Yoshimoto M, Takahashi H (2003) Lewy bodies in Betz cells of the motor cortex in a patient with Parkinson's disease. Acta Neuropathologica 105:189-192
Smeyne M, Jiao Y, Shepherd KR, Smeyne RJ (2005) Glia cell number modulates sensitivity to MPTP in mice. Glia 52:144-152
Marchetti B, Serra PA, L'Episcopo F, Tirolo C, Caniglia S, Testa N, Cioni S, Gennuso F, Rocchitta G, Desole MS, Mazzarino MC, Miele E, Morale MC (2005) Hormones are key actors in gene x environment interactions programming the vulnerability to Parkinson's disease: glia as a common final pathway. Ann N Y Acad Sci 1057:296-318
Morale MC, Serra PA, L'Episcopo F, Tirolo C, Caniglia S, Testa N, Gennuso F, Giaquinta G, Rocchitta G, Desole MS, Miele E, Marchetti B (2006) Estrogen, neuroinflammation and neuroprotection in Parkinson's disease: glia dictates resistance versus vulnerability to neurodegeneration. Neuroscience (In press)
Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhou Y, Hong JS, Zhang J (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J 19:533-542
Benjamini Y, Hochberg Y (2000) On the adaptive control of the false discovery fate in multiple testing with independent statistics. J Educ Behav Stat 25:60-83
Blalock EM, Chen KC, Stromberg AJ, Norris CM, Kadish I, Kraner SD, Porter NM, Landfield PW (2005) Harnessing the power of gene microarrays for the study of brain aging and Alzheimer's disease: statistical reliability and functional correlation. Ageing Res Rev 4:481-512
Hastie T, Tibshirani R, Eisen MB, Alizadeh A, Levy R, Staudt L, Chan WC, Botstein D, Brown P (2000) 'Gene shaving' as a method for identifying distinct sets of genes with similar expression patterns. Genome Biol 1:RESEARCH0003
Alter O, Brown PO, Botstein D (2000) Singular value decomposition for genome-wide expression data processing and modeling. Proc Natl Acad Sci USA 97:10101-10106
Gaspari M, Falkenberg M, Larsson NG, Gustafsson CM (2004) The mitochondrial RNA polymerase contributes critically to promoter specificity in mammalian cells. EMBO J 23:4606-4614
Wilson SM, Bhattacharyya B, Rachel RA, Coppola V, Tessarollo L, Householder DB, Fletcher CF, Miller RJ, Copeland NG, Jenkins NA (2002) Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nat Genet 32:420-425
Hardy J, Cookson MR, Singleton A (2003) Genes and parkinsonism. Lancet Neurol 2:221-228
Hattori N, Kobayashi H, Sasaki-Hatano Y, Sato K, Mizuno Y (2003) Familial Parkinson's disease: a hint to elucidate the mechanisms of nigral degeneration. J Neurol 250(Suppl 3):III2-III10
Lim KL, Dawson VL, Dawson TM (2003) The cast of molecular characters in Parkinson's disease: felons, conspirators, and suspects. Ann N Y Acad Sci 991:80-92
Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson's disease. Bioessays 24:308-318
McNaught KS, Perl DP, Brownell AL, Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann Neurol 56:149-162
Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K (2003) The role of alpha-synuclein in Parkinson's disease: insights from animal models. Nat Rev Neurosci 4:727-738
McNaught KS, Belizaire R, Jenner P, Olanow CW, Isacson O (2002) Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson's disease. Neurosci Lett 326:155-158
Sullivan PG, Dragicevic NB, Deng JH, Bai Y, Dimayuga E, Ding Q, Chen Q, Bruce-Keller AJ, Keller JN (2004) Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover. J Biol Chem 279:20699-20707
Nakaso K, Yoshimoto Y, Yano H, Takeshima T, Nakashima K (2004) p53-mediated mitochondrial dysfunction by proteasome inhibition in dopaminergic SH-SY5Y cells. Neurosci Lett 354:213-216
Kikuchi S, Shinpo K, Tsuji S, Takeuchi M, Yamagishi S, Makita Z, Niino M, Yabe I, Tashiro K (2003) Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons. Brain Res 964:228-236
Hoglinger GU, Carrard G, Michel PP, Medja F, Lombes A, Ruberg M, Friguet B, Hirsch EC (2003) Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease. J Neurochem 86:1297-1307
Tanaka Y, Engelender S, Igarashi S, Rao RK, Wanner T, Tanzi RE, Sawa A, Dawson L, Dawson TM, Ross CA (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 10:919-926
Mattila PM, Rinne JO, Helenius H, Dickson DW, Roytta M (2000) Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease. Acta Neuropathologica 100:285-290
