Abstract
We have used brain tissue from clinically well-documented and neuropathologically confirmed cases of sporadic Parkinson’s disease to establish the transcriptomic expression profile of the medial and lateral substantia nigra. In addition, the superior frontal cortex was analyzed in a subset of the same cases. DNA oligonucleotide microarrays were employed, which provide whole human genome coverage. A total of 570 genes were found to be differentially regulated at a high level of significance. A large number of differentially regulated expressed sequence tags were also identified. Levels of mRNA sequences encoded by genes of key interest were validated by means of quantitative real-time polymerase chain reaction (PCR). Comparing three different normalization procedures, results based on the recently published GeneChip Robust Multi Array algorithm were found to be the most accurate predictor of real-time PCR results. Several new candidate genes which map to PARK loci are reported. In addition, the DNAJ family of chaperones is discussed in the context of Parkinson’s disease pathogenesis.
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Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047
Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108
Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) Alpha-synuclein locus triplication causes Parkinson’s disease. Science 302:841
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
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
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
Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33:85–89
Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607
Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114:2283–2301
Moran LB, Duke DC, Turkheimer FE, Banati RB, Graeber MB (2004) Towards a transcriptome definition of microglial cells. Neurogenetics 5:95–108
Wu Z, Irizarry RA (2004) Preprocessing of oligonucleotide array data. Nat Biotechnol 22:656–658
Hsiao LL, Dangond F, Yoshida T, Hong R, Jensen RV, Misra J, Dillon W, Lee KF, Clark KE, Haverty P, Weng Z, Mutter GL, Frosch MP, Macdonald ME, Milford EL, Crum CP, Bueno R, Pratt RE, Mahadevappa M, Warrington JA, Stephanopoulos G, Stephanopoulos G, Gullans SR (2001) A compendium of gene expression in normal human tissues. Physiol Genomics 7:97–104
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034
Peirson SN, Butler JN, Foster RG (2003) Experimental validation of novel and conventional approaches to quantitative real-time PCR data analysis. Nucleic Acids Res 31(14):e73
Zhang Y, James M, Middleton FA, Davis RL (2005) Transcriptional analysis of multiple brain regions in Parkinson’s disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet B Neuropsychiatr Genet 137:5–16
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29
Kosel S, Egensperger R, von Eitzen U, Mehraein P, Graeber MB (1997) On the question of apoptosis in the parkinsonian substantia nigra. Acta Neuropathol (Berl) 93:105–108
Graeber MB, Grasbon-Frodl E, Abell-Aleff P, Kösel S (1999) Nigral neurons are likely to die of a mechanism other than classical apoptosis in Parkinson’s disease. Parkinsonism Relat Disord 5:187–192
Hicks AA, Pétursson H, Jónsson T, Stefánsson H, Jóhannsdóttir HS, Sainz J, Frigge ML, Kong A, Gulcher JR, Stefánsson K, Sveinbjörnsdóttir S (2002) A susceptibility gene for late-onset idiopathic Parkinson’s disease. Ann Neurol 52:549–555
Oliveira SA, Li YJ, Noureddine MA, Züchner S, Qin X, Pericak-Vance MA, Vance JM (2005) Identification of risk and age-at-onset genes on chromosome 1 p in Parkinson disease. Am J Hum Genet 77:252–264
Grunblatt E, Mandel S, Jacob-Hirsch J, Zeligson S, Amariglo N, Rechavi G, Li J, Ravid R, Roggendorf W, Riederer P, Youdim MB (2004) Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J Neural Transm 111:1543–1573
Hauser MA, Li YJ, Xu H, Noureddine MA, Shao YS, Gullans SR, Scherzer CR, Jensen RV, McLaurin AC, Gibson JR, Scott BL, Jewett RM, Stenger JE, Schmechel DE, Hulette CM, Vance JM (2005) Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. Arch Neurol 62:917–921
Gerace L, Gilmore R, Johnson A, Lazarow P, Neupert W, O’Shea E, Weis K (2002) Intracellular compartments and protein sorting. In: Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (eds) Molecular biology of the cell, 4th edn. Garland, New York
Sai X, Kawamura Y, Kokame K, Yamaguchi H, Shiraishi H, Suzuki R, Suzuki T, Kawaichi M, Miyata T, Kitamura T, De Strooper B, Yanagisawa K, Komano H (2002) Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. J Biol Chem 277:12915–12920
Holtz WA, O’Malley KL (2003) Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. Biol Chem 278:19367–19377
van Laar T, van der Eb AJ, Terleth C (2001) Mif1: a missing link between the unfolded protein response pathway and ER-associated protein degradation? Curr Protein Pept Sci 2:169–190
van Laar T, van der Eb AJ, Terleth C (2002) A role for Rad23 proteins in 26S proteasome-dependent protein degradation? Mutat Res 499:53–61
Tanahashi-Hori T, Tanahashi N, Tanaka K, Chiba T (2003) Conditional knockdown of proteasomes results in cell-cycle arrest and enhanced expression of molecular chaperones Hsp70 and Hsp40 in chicken DT40 cells. J Biol Chem 278:16237–16243
Inada H, Izawa I, Nishizawa M, Fujita E, Kiyono T, Takahashi T, Momoi T, Inagaki M (2001) Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J Cell Biol 155:415–426
Acknowledgements
We are grateful to the brain donors and their families for the provision of brain tissue for research. This work was funded through a programme grant from the UK Parkinson’s Disease Society. We are grateful to the Parkinson’s Disease Society Tissue Bank at Imperial College London, funded by the Parkinson’s Disease Society of the UK, registered charity 948776. We would also like to thank the UK Multiple Sclerosis Tissue Bank at Imperial College London. Use of an Affymetrix node in the Department of Neuropathology, funded by the Trustees of the Corsellis Collection, is gratefully acknowledged. The authors would like to thank Dr. Stuart Peirson for his expert advice on the qRT-PCR analysis and Dr. Geraint Barton from the Bioinformatics Support Service, Imperial College London, for his advice and for the reading of the manuscript.
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Supplemental Figure (PDF 374 KB): Pathway relationships of the genes listed in Table 3. Green/red, positive/negative regulatory influence. Lilac, binding
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Moran, L.B., Duke, D.C., Deprez, M. et al. Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson’s disease. Neurogenetics 7, 1–11 (2006). https://doi.org/10.1007/s10048-005-0020-2
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DOI: https://doi.org/10.1007/s10048-005-0020-2