Genetic causes of Parkinson’s disease: extending the pathway

  • O. Riess
  • R. Krüger
  • H. Hochstrasser
  • A. S. Soehn
  • S. Nuber
  • T. Franck
  • D. Berg
Part of the Journal of Neural Transmission. Supplementa book series (NEURALTRANS, volume 70)


The functional characterization of identified disease genes in monogenic forms of Parkinson’s disease (PD) allows first insights into molecular pathways leading to neurodegeneration and dysfunction of the nigrostriatal system. There is increasing evidence that disturbance of the ubiquitin proteasome pathway is one important feature of this process underscoring the relevance of protein misfolding and accumulation in the neurodegenerative process of PD. Other genes are involved in mitochondrial homeostasis and still others link newly identified signalling pathways to the established paradigm of oxidative stress in PD. Additional factors are posttranslational modifications of key proteins such as phosphorylation. Also, molecular data support the role of altered iron metabolism in PD. Here we describe known genes and novel genetic susceptibility factors and define their role in neurodegeneration.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bandopadhyay R, Kingsbury AE, Muqit MM, Harvey K, Reid AR, Kilford L, Engelender S, Schlossmacher MG, Wood NW, Latchman DS, Harvey RJ, Lees AJ (2005) Synphilin-1 and parkin show overlapping expression patterns in human brain and form aggresomes in response to proteasomal inhibition. Neurobiol Dis 20: 401–411PubMedCrossRefGoogle Scholar
  2. Beal MF (2000) Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 23: 298–304PubMedCrossRefGoogle Scholar
  3. Beilina A, Brug M, Ahmad R, Kesavapany S, Miller DW, Petsko GA, Cookson MR (2005) Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. PNAS 102: 5703–5708PubMedCrossRefGoogle Scholar
  4. Berg D, Roggendorf W, Schröder U, Klein R, Tatschner T, Benz P, Tucha O, Preier M, Lange KW, Reiners K, Gerlach M, Becker G (2002) Echogenicity of the substantia nigra — association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 59: 999–1005PubMedCrossRefGoogle Scholar
  5. Berg D, Holzmann C, Riess O (2003a) 14-3-3 proteins in the nervous system. Nat Neurosci 4: 752–762CrossRefGoogle Scholar
  6. Berg D, Riess O, Bornemann A (2003b) Specification of 14-3-3 proteins in Lewy bodies. Ann Neurol 54: 135PubMedCrossRefGoogle Scholar
  7. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MCJ, Squitieri F, Ibanez P, Joosse M, can 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: 256–259PubMedCrossRefGoogle Scholar
  8. Bosio S, De Gobbi M, Roetto A, Zecchina G, Leonardo E, Rizzetto M, Lucetti C, Petrozzi L, Bonuccelli U, Camaschella C (2002) Anemia and iron overload due to compound heterozygosity for novel ceruloplasmin mutation. Blood 100: 2246–2248PubMedCrossRefGoogle Scholar
  9. Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. PNAS 101: 9103–9108PubMedCrossRefGoogle Scholar
  10. Chung KKK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the α-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7: 1144–1150PubMedCrossRefGoogle Scholar
  11. Curtis ARJ, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nature Genet 28: 350–354PubMedCrossRefGoogle Scholar
  12. Deplazes J, Schobel K, Hochstrasser H, Bauer P, Walter U, Behnke S, Spiegel J, Becker G, Riess O, Berg D (2004) Screening for mutations of the IRP2 gene in Parkinson’s disease patients with hyperechogenicity of the substantia nigra. J Neural Transm 111: 15–521CrossRefGoogle Scholar
  13. Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF, Dawson VL, Dawson TM, Ross CA (1999) Synphilin-1 associated with α-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 22: 110–114PubMedCrossRefGoogle Scholar
  14. Farrer M, Wavrant-De Vrieze F, Crook R, Boles L, Perez-Tur J, Hardy J, Johnson WG, Steele J, Maraganore D, Gwinn K, Lynch T (1998) Low frequency of alpha-synuclein mutations in familial Parkinson’s disease. Ann Neurol 43: 394–397PubMedCrossRefGoogle Scholar
  15. Felletschin B, Bauer P, Walter U, Behnke S, Spiegel J, Csoti I, Sommer U, Zeiler B, Becker G, Riess O, Berg D (2003) Screening for mutations of the ferritin light and heavy genes in Parkinson’s disease patients with hyperechogenicity of the substantia nigra. Neurosci Lett 352: 53–56PubMedCrossRefGoogle Scholar
  16. Gasser T, Müller-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: 262–265PubMedCrossRefGoogle Scholar
  17. Gearan T, Castillo OA, Schwarzschild MA (2001) The parkinsonian neurotoxin, MPP+ induces phosphorylated c-Jun in dopaminergic neurons of mesencephalic cultures. Parkinsonism Relat Disord 8: 19–22PubMedCrossRefGoogle Scholar
  18. Giasson BI, Uryu K, Trojanowski JQ, Lee VM (1999) Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro. J Biol Chem 274: 7619–7622PubMedCrossRefGoogle Scholar
  19. Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 278: 43628–43635PubMedCrossRefGoogle Scholar
  20. Greene JC, Whitworth AJ, Kuro I, Andrews LA, Feanny MB, Pallanck LI (2003) Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Proc Natl Acad Sci 100: 4078–4083PubMedCrossRefGoogle Scholar
  21. Hampshire DJ, Roberts E, Crow Y, Bond J, Mubaidin A, Wriekat AL, Al-Din A, Woods CG (2001) Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36. J Med Genet 38: 680–682PubMedCrossRefGoogle Scholar
  22. Helenius A, Aebi M (2004) Roles of N-linked glycans in the endoplasmatic reticulum. Annu Rev Biochem 73: 1019–1049PubMedCrossRefGoogle Scholar
  23. 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: 549–555PubMedCrossRefGoogle Scholar
  24. Hochstrasser H, Bauer P, Walter U, Behnke S, Spiegel J, Csoti I, Zeiler B, Bornemann A, Pahnke J, Becker G, Riess O, Berg D (2004) Ceruloplasmin gene variations and substantia nigra hyperechogenicity in Parkinson disease. Neurology 63: 1912–1917PubMedGoogle Scholar
  25. Hochstrasser H, Tomiuk J, Walter U, Behnke S, Spiegel J, Krüger R, Becker G, Riess O, Berg D (2005) Functional relevance of ceruloplasmin mutations in Parkinson’s disease. FASEB J 19: 1851–1853PubMedGoogle Scholar
  26. Hofmann RM, Pickart CM (1999) Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96: 27936–27943CrossRefGoogle Scholar
  27. Itier JM et al. (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 13: 2277–2291CrossRefGoogle Scholar
  28. Kawamoto Y, Akiguchi I, Nakamura S, Honjyo Y, Shibasaki H, Budka H (2002) 14-3-3 proteins in Lewy bodies in Parkinson’s disease and diffuse Lewy body disease brains. J Neuropathol Exp Neurol 61: 245–253PubMedGoogle Scholar
  29. 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: 605–608PubMedCrossRefGoogle Scholar
  30. Klomp LW, Gitlin JD (1996) Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum Mol Genet 5: 1989–1996PubMedCrossRefGoogle Scholar
  31. Kohno S, Miyajima H, Takahashi Y (1999) Aceruloplasminemia with a novel mutation associated with parkinsonism. Neurogenetics 2: 237–238CrossRefGoogle Scholar
  32. Krüger R, Vieira-Saecker AM, Kuhn W, Berg D, Müller T, Kühnl N, Fuchs GA, Storch A, Hungs M, Woitalla D, Przuntek H, Epplen JT, Schöls L, Riess O (1999) Increased susceptibility to sporadic Parkinson’s disease by a certain combined alpha-synuclein/apolipoprotein E genotype. Ann Neurol 45: 611–617PubMedCrossRefGoogle Scholar
  33. Kulich SM, Chu CT (2001) Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: implications for Parkinson’s disease. J Neurochem 77: 1058–1066PubMedCrossRefGoogle Scholar
  34. LaVaute T, Smith S, Cooperman S (2001) Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet 27: 209–214PubMedCrossRefGoogle Scholar
  35. Lee G, Tanaka M, Park K, Lee SS, Kim YM, Junn E, Lee S-H, Mouradian MM (2004) Casein kinase II-mediated phosphorylation regulates alpha-synuclein/synphilin-1 interaction and inclusion body formation. J Biol Chem 279: 6834–6839PubMedCrossRefGoogle Scholar
  36. 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 P, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395: 451–452PubMedCrossRefGoogle Scholar
  37. Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, Bornemann A, Riess O, Ross CA, Rott R, Engelender S (2004) Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson’s disease. Proc Natl Acad Sci 101: 5500–5505PubMedCrossRefGoogle Scholar
  38. Liu Y, Fallon L, Lashuel HA et al. (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility. Cell 111: 209–218PubMedCrossRefGoogle Scholar
  39. Marx FP, Holzmann C, Strauss KM, Li L, Eberhardt O, Gerhardt E, Cookson MR, Hernandez D, Farrer MJ, Kachergus J, Engelender S, Ross CA, Berger K, Schöls L, Schulz JB, Riess O, Krüger R (2003) Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson’s disease. Hum Mol Genet 12: 1223–1231PubMedCrossRefGoogle Scholar
  40. Murray IVJ, Medford MA, Guan HP, Rueter SM, Trojanowski JQ, Lee VMY (2003) Synphilin in normal human brains and in synucleopathies: studies with new antibodies. Acta Neuropathol 105: 177–184PubMedGoogle Scholar
  41. 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, Saenz Pena A, 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: 595–600PubMedCrossRefGoogle Scholar
  42. Palacino JJ, Sabi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 324: 18614–18622CrossRefGoogle Scholar
  43. Pankratz N, Nichols WC, Uniacke SK, Halter C, Rudolph A, Shults C, Conneally PM, Foroud T, and the Parkinson Study Group (2003) Significant linkage of Parkinson disease to chromosome 2q36-37. Am J Hum Genet 72: 1053–1057PubMedCrossRefGoogle Scholar
  44. Pesah Y, Ham T, Burgess H, Middlebrooks B, Verstreken P, Zhou Y, Harding M, Bellen H, Marodon G (2004) Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131: 2183–2194PubMedCrossRefGoogle Scholar
  45. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa T, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Iorio GD, Golbe LI, Nussbaum RL (1997) Mutation in alpha-synuclein gene identified in families with Parkinson’s disease. Nature 276: 2045–2047Google Scholar
  46. Ruprecht-Dörfler P, Berg D, Tucha O, Benz P, Meier-Meitinger M, Alders GL, Lange KW, Becker G (2003) Echogenicity of the substantia nigra in relatives of patients with sporadic Parkinson’s disease. NeuroImage 18: 416–422PubMedCrossRefGoogle Scholar
  47. Sato S, Chiba T, Sakata E, Kato K, Mizuno Y, Hattori N, Tanaka K (2005) 14-3-3Z is a novel regulator of parkin ubiquitin ligase. EMBO J: 1–11Google Scholar
  48. Schapira AH (1999) Mitochondrial involvement in Parkinson’s disease, Huntington’s disease, hereditary spastic paraplegia and Friedreich’s ataxia. Biochim Biophys Acta 1410: 159–170PubMedCrossRefGoogle Scholar
  49. Shen J (2004) Protein kinases linked to the pathogenesis of Parkinson’s disease. Neuron 44: 575–577PubMedCrossRefGoogle Scholar
  50. 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: 841PubMedCrossRefGoogle Scholar
  51. Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388: 839–840PubMedCrossRefGoogle Scholar
  52. Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Müller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Krüger R (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 14: 2099–2111PubMedCrossRefGoogle Scholar
  53. Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5: 213–218PubMedCrossRefGoogle Scholar
  54. Tan EK, Matsuura T, Nagamitsu S, Khajavi M, Jankovic J, Ashizawa T (2000) Polymorphism of NACP-Rep1 in Parkinson’s disease: an etiologic link with essential tremor? Neurology 54: 1195–1198PubMedGoogle Scholar
  55. Thompson K, Menzies S, Muckenthaler M (2003) Mouse brains deficient in H-ferritin have normal iron concentration but a protein profile of iron deficiency and increased evidence of oxidative stress. J Neurosci Res 71: 46–63PubMedCrossRefGoogle Scholar
  56. Toska K, Kleppe R, Armstrong CG, Morrice NA, Cohen P, Haavik J (2002) Regulation of tyrosine hydroxylase by stress-activated protein kinases. J Neurochem 83: 775–783PubMedCrossRefGoogle Scholar
  57. Touchman JW, Dehejia A, Chiba-Falek O, Cabin DE, Schwartz JR, Orrison BM, Polymeropoulos MH, Nussbaum RL (2001) Human and mouse alpha-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element. Genome Res 11: 78–86PubMedCrossRefGoogle Scholar
  58. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K, Gispert S, Ali Z, Turco DD, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzales-Maldonado R, Deller R, 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: 1158–1160PubMedCrossRefGoogle Scholar
  59. Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H (2004) Overexpression of alpha-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of alpha-synuclein and activation of caspase-9: resemblance to pathogenic changes in Parkinson’s disease. J Neurochem 91: 451–461PubMedCrossRefGoogle Scholar
  60. Yamamoto A, Friedlein A, Imai Y, Takahashi R, Kahle PJ, Haass C (2005) Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity. J Biol Chem 280: 3390–3399PubMedCrossRefGoogle Scholar
  61. 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, Müller-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: 601–607PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • O. Riess
    • 1
  • R. Krüger
    • 2
  • H. Hochstrasser
    • 1
  • A. S. Soehn
    • 1
  • S. Nuber
    • 1
  • T. Franck
    • 1
  • D. Berg
    • 1
    • 2
  1. 1.Department of Medical GeneticsUniversity of TuebingenTuebingenGermany
  2. 2.Hertie Institute, Department of NeurologyUniversity of TuebingenGermany

Personalised recommendations