[en] The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be up-regulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly(ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.
Research Center/Unit :
Imperial College London
Disciplines :
Neurology
Author, co-author :
Moran, L. B.; Imperial College London > Department of Neuropathology
Croisier, E.; Imperial College London > Department of Neuropathology
Duke, D. C.; Imperial College London > Department of Neuropathology
Kalaitzakis, M. E.; Imperial College London > Department of Neuropathology
Roncaroli, F.; 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 Biology
Pearce, R. K. B.; Imperial College London > Department of Neuropathology
Graeber, M. B.; Imperial College London > Department of Neuropathology
Language :
English
Title :
Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra.
Publication date :
2007
Journal title :
Acta Neuropathologica
ISSN :
0001-6322
eISSN :
1432-0533
Publisher :
Springer Verlag, New York, United States - New York
Volume :
113
Issue :
3
Pages :
253-63
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Parkinson’s Disease Society of the United Kingdom, registered charity 948776.
Agid Y, Ruberg M, Javoy-Agid F, Hirsch E, Raisman-Vozari R, Vyas S, Faucheux B, Michel P, Kastner A, Blanchard V (1993) Are dopaminergic neurons selectively vulnerable to Parkinson's disease? Adv Neurol 60:148-164
Bennett MC (2005) The role of alpha-synuclein in neurodegenerative diseases. Pharmacol Ther 105:311-331
Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389-1392
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-1gene associated with autosomal recessive early-onset parkinsonism. Science 299:256-259
Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24:197-211
Cha GH, Kim S, Park J, Lee E, Kim M, Lee SB, Kim JM, Chung J, Cho KS (2005) Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc Natl Acad Sci USA 102:10345-10350
Chiba-Falek O, Kowalak JA, Smulson ME Nussbaum RL (2005) Regulation of alpha-synuclein expression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene. Am J Hum Genet 76:478-492
Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: Implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144-1150
Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB (2005) Microglial inflammation in the parkinsonian substantia nigra: Relationship to alpha-synuclein deposition. J Neuroinflamm 2:14
Croisier E, Elfant D, Deprez M, Goldring K, Dexter DT, Pearce RKB, Graeber MB, Roncaroli F (2006) Comparative study of commercially available anti-alpha-synuclein antibodies. Neuropathol Appl Neurobiol 32:1365-2990
Croisier E, Graeber MB (2006) Glial degeneration and reactive gliosis in alpha-synucleinopathies: The emerging concept of primary gliodegeneration. Acta Neuropathol (Berl) 112:517-530
D'Amours D, Desnoyers S, D'Silva I, Poirier GG (1999) Poly(ADP-ribosylation reactions in the regulation of nuclear functions. Biochem J 342:249-268
Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413-426
de Rijk MC, Tzourio C, Breteler MM, Dartigues JF, Amaducci, Lopez-Pousa S, Manubens-Bertran JM, Alperovitch A, Rocca WA (1997) Prevalence of parkinsonism and Parkinson's disease in Europe: The EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson's disease. J Neurol Neurosurg Psychiatr 62:10-15
Duke DC, Moran LB, Kalaitzakis ME, Deprez M, Dexter DT, Pearce RK, Graeber MB (2006) Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson's disease. Neurogenetics 7:139-148
Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F (2002) A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 51:296-301
Galvin JE (2006) Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: A case for the selective vulnerability of the substantia nigra. Acta Neuropathol (Berl) 112:115-126
Gasser T, Muller-Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, Bonifati V, Bereznai B, Fabrizio E, Vieregge P, Horstmann RD (1998) A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nat Genet 18:262-265
Giasson BI, Lee VM (2003) Are ubiquitination pathways central to Parkinson's disease? Cell 114:1-8
Gottfried Y, Rotem A, Lotan R, Steller H, Larisch S (2004) The mitochondrial ARTS protein promotes apoptosis through targeting XIAP. EMBO J 23:1627-1635
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
Hicks AA, Petursson H, Jonsson T, Stefansson H, Johannsdottir HS, Sainz J, Frigge ML, Kong A, Gulcher JR, Stefansson K, Sveinbjornsdottir S (2002) A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol 52:549-555
Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165:347-356
Huang Y, Cheung L, Rowe D, Halliday G (2004) Genetic contributions to Parkinson's disease. Brain Res Brain Res Rev 46:44-70
Ihara M, Tomimoto H, Kitayama H, Morioka Y, Akiguchi I, Shibasaki H, Noda M, Kinoshita M (2003) Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies. J Biol Chem 278:24095-24102
Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891-902
Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, Takahashi R (2002) CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Mol Cell 10:55-67
Jenner P, Olanow CW (1998) Understanding cell death in Parkinson's disease. Ann Neurol 44:S72-S84
Jiang H, Ren Y, Zhao J, Feng J (2004) Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum Mol Genet 13:1745-1754
Kingsbury AE, Daniel SE, Sangha H, Eisen S, Lees AJ, Foster OJ (2004) Alteration in alpha-synuclein mRNA expression in Parkinson's disease. Mov Disord 19:162-170
Kinoshita A, Kinoshita M, Akiyama H, Tomimoto H, Akiguchi I, Kumar S, Noda M, Kimura J (1988) Identification of septins in neurofibrillary tangles in Alzheimer's disease. Am J Pathol 153:1551-1560
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
Koh DW, Dawson TM, Dawson VL (2005) Mediation of cell death by poly(ADP-ribose) polymerase-1. Pharmacol Res 52:5-14
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
Leroy E, Boyer R, Polymeropoulos MH (1998) Intron-exon structure of ubiquitin c-terminal hydrolase-L1. DNA Res 5:397-400
Luo Y, Umegaki H, Wang X, Abe R, Roth GS (1998) Dopamine induces apoptosis through an oxidation-involved SAPK/JNK activation pathway. J Biol Chem 273:3756-3764
Marazziti D, Golini E, Mandillo S, Magrelli A, Witke W, Matteoni R, Tocchini-Valentini GP (2004) Altered dopamine signalling and MPTP resistance in mice lacking the Parkinson's disease-associated GPR37/ parkin-associated endothelin-like receptor. Proc Natl Acad Sci USA 101:10189-10194
Matsumine H, Saito M, Shimoda-Matsubayashi S, Tanaka H, Ishikawa A, Nakagawa-Hattori Y, Yokochi M, Kobayashi T, Igarashi S, Takano H, Sanpei K, Koike R, Mori H, Kondo T, Mizutani Y, Schaffer AA, Yamamura Y, Nakamur S, Kuzuhara S, Tsuji S, Mizuno Y (1997) Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27. Am J Hum Genet 60:588-596
McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD (2005) Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: Male toxicity, female protection. J Cereb Blood Flow Metab 25:502-512
McNaught KS, Olanow CW (2003) Proteolytic stress: A unifying concept for the etiopathogenesis of Parkinson's disease. Ann Neurol 53:S73-S84
Miller RM, Kiser GL, Kaysser-Kranich TM, Lockner RJ, Palaniappan C, Federoff HJ (2006) Robust dysregulation of gene expression in substantia nigra and striatum in Parkinson's disease. Neurobiol Dis 21:305-313. Epub 6 September 2005
Moran LB, Duke DC, Turkheimer FE, Banati RB, Graeber MB (2004) Towards a transcriptome definition of microglial cells. Neurogenetics 5:95-108
Moran LB, Duke DC, Deprez M, Dexter DT, Pearce RKB, Graeber MB (2006a) Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson's disease. Neurogenetics 7:1-11
Moran LB, Hickey L, Duke DC, Derkacs M, Michael GJ, Croisier E, Dexter DT, Pearce RKB, Graeber MB (2006b) Expression profiling demonstrates cerebral cortex involvement in Parkinson's disease. In: 36th Annual Meeting of the Society for Neuroscience, Atlanta, GA, 14-18 October 2006. Society for Neuroscience Abstracts: 173.2/FF26
Mouradian MM (2002) Recent advances in the genetics and pathogenesis of Parkinson disease. Neurology 58:179-185
Neystat M, Lynch T, Przedborski S, Kholodilov N, Rzhetskaya M, Burke RE (1999) Alpha-synuclein expression in substantia nigra and cortex in Parkinson's disease. Mov Disord 14:417-422
Oluwatosin-Chigbu Y, Robbins A, Scott CW, Arriza JL, Reid JD, Zysk JR (2003) Parkin suppresses wild-type alpha-synuclein-induced toxicity in SHSY-5Y cells. Biochem Biophys Res Commun 309:679-884
Orth M, Schapira AH (2002) Mitochondrial involvement in Parkinson's disease. Neurochem Int 40:533-541
Pankratz N, Nichols WC, Uniacke SK, Halter C, Rudolph A, Shults C, Conneally PM, Foroud T, The Parkinson Study Group (2003) Significant linkage of Parkinson disease to chromosome 2q36-37. Am J Hum Genet 72:1053-1057
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:e73
Pieper AA, Verma A, Zhang J, Snyder SH (1999) Poly (ADP-ribose) polymerase, nitric oxide and cell death. Trends Pharmacol Sci 20:171-181
Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC (1996) Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science 274:1197-1199
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos E.S, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson W.G, 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
Ren Y, Zhao J, Feng J (2003) Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci 23:3316-3324
Schapira AH (1998) Human complex I defects in neurodegenerative diseases. Biochim Biophys Acta 1364:261-270
Sherer T.B, Betarbet R, Greenamyre JT (2002) Environment, mitochondria, and Parkinson's disease. Neuroscientist 8:192-197
Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R. Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: Implications for Parkinson's disease. Science 293:263-269
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) α-synuclein locus triplication causes Parkinson's disease. Science 302:841
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469-6473
Storr HL, Clark AJ, Priestley JV, Michael GJ (2005) Identification of the sites of expression of triple A syndrome mRNA in the rat using in situ hybridisation. Neuroscience 131:113-123
Sveinbjornsdottir S, Hicks AA, Jonsson T, Petursson H, Gugmundsson G, Frigge ML, Kong A, Gulcher JR, Stefansson K (2000) Familial aggregation of Parkinson's disease in Iceland. N Engl J Med 343:1765-1770
Takahashi S, Inatome R, Yamamura H, Yanagi S (2003) Isolation and expression of a novel mitochondrial septin that interacts with RMP/CRAM in the developing neurones. Genes Cells 8:81-93
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
van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P (2001) Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Hum Genet 69:629-634
Wersinger C, Sidhu A (2003) Attenuation of dopamine transporter activity by alpha-synuclein. Neurosci Lett 340:189-192
Wu Z, Irizarry RA (2004) Preprocessing of oligonucleotide array data. Nat Biotechnol 22:656-658
Ying W, Sevigny MB, Chen Y, Swanson RA (2001) Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death. Proc Natl Acad Sci USA 98:12227-12232
Ying W, Chen Y, Alano CC, Swanson RA (2002) Tricarboxylic acid cycle substrates prevent PARP-mediated death of neurons and astrocytes. J Cereb Blood Flow Metab 22:774-779
Yoo BC, Fountoulakis M, Dierssen M, Lubec G (2001) Expression patterns of chaperone proteins in cerebral cortex of the fetus with Down syndrome: Dysregulation of T-complex protein 1. J Neural Transm Suppl 61:321-334
Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez TE, del Ser T, Munoz DG, de Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164-173
Ziegler M, Oei SL (2001) A cellular survival switch: poly(ADP-ribosyl)ation stimulates DNA repair and silences transcription. Bioessays 23:543-548
Zhang Y, Dawson VL, Dawson TM (2000) Oxidative stress and genetics in the pathogenesis of Parkinson's disease. Neurobiol Dis 7:240-250
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. Erratum in: Am J Med Genet B Neuropsychiatr Gene 139:122
