Acta Neuropathologica

, Volume 115, Issue 1, pp 87–95 | Cite as

α-Synucleinopathy models and human neuropathology: similarities and differences

  • Philipp J. KahleEmail author


Point mutations and genomic multiplications in the α-synuclein (αSYN) gene cause autosomal-dominant Parkinson’s disease. Moreover, αSYN fibrils are the major component of Lewy bodies, the neuropathological hallmarks of Parkinson’s disease and dementia with Lewy bodies as well as of glial cytoplasmic inclusions in multiple system atrophy. These diseases are collectively referred to as α-synucleinopathies. Cellular mechanisms regulating αSYN fibril formation and toxicity are intensely studied in vitro, and in cell culture and diverse animal models. Specific neuropathology was achieved in transgenic mouse models using several promoters to express human wild-type and mutant αSYN in brain regions affected by the various α-synucleinopathies. Somatodendritic accumulation of the transgenic αSYN with neuritic distortions was a common finding. The nigrostriatal dopaminergic projections were surprisingly resistant to α-synucleinopathy in transgenic mice, although they tended to be more vulnerable to neurotoxins. In a few mouse models, αSYN aggregated in an age-dependent manner into genuine fibrillar amyloid. Brain region selective αSYN neuropathology correlated with specific behavioral impairments, such as locomotor dysfunction and cognitive decline. Thus, the αSYN fibrillization process is tightly linked to neuropathology. The role and thus therapeutic potential of post-translational modifications (ubiquitinylation, oxidation, phosphorylation, truncation) and modifier genes on αSYN neuropathology can now be assessed in valid transgenic mouse models of α-synucleinopathies.


Synuclein Transgenic mice Parkinson’s disease Dementia with Lewy bodies Multiple system atrophy 



Own work cited here was supported by the Deutsche Forschungsgemeinschaft (grants HA 1737/4 and SFB A1) and the German National Genome Research Network (NGFN). Immunostainings were kindly provided by Manuela Neumann. I thank Wolfdieter Springer, Susanne Schöbel and Silke Nuber for their comments and suggestions.


  1. 1.
    Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho W-H, Castillo PE, Shinsky N, Garcia Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252PubMedCrossRefGoogle Scholar
  2. 2.
    Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M, Diep L, Keim PS, Shen X, Chataway T, Schlossmacher MG, Seubert P, Schenk D, Sinha S, Gai WP, Chilcote TJ (2006) Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752PubMedCrossRefGoogle Scholar
  3. 3.
    Arima K, Uéda K, Sunohara N, Arakawa K, Hirai S, Nakamura M, Tonozuka-Uehara H, Kawai M (1998) NACP/α-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy. Acta Neuropathol 96:439–444PubMedCrossRefGoogle Scholar
  4. 4.
    Baba M, Nakajo S, Tu P-H, Tomita T, Nakaya K, Lee VM-Y, Trojanowski JQ, Iwatsubo T (1998) Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884PubMedGoogle Scholar
  5. 5.
    Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC (2005) α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123:383–396PubMedCrossRefGoogle Scholar
  6. 6.
    Chartier-Harlin M-C, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destée A (2004) α-Synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364:1167–1169PubMedCrossRefGoogle Scholar
  7. 7.
    Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, LaBaer J, Rochet J-C, Bonini NM, Lindquist S (2006) α-Synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313:324–328PubMedCrossRefGoogle Scholar
  8. 8.
    Dalfó E, Gómez-Isla T, Rosa JL, Nieto Bodelón M, Cuadrado Tejedor M, Barrachina M, Ambrosio S, Ferrer I (2004) Abnormal α-synuclein interactions with Rab proteins in α-synuclein A30P transgenic mice. J Neuropathol Exp Neurol 63:302–313PubMedGoogle Scholar
  9. 9.
    Di Rosa G, Puzzo D, Sant’Angelo A, Trinchese F, Arancio O (2003) α-Synuclein: between synaptic function and dysfunction. Histol Histopathol 18:1257–1266PubMedGoogle Scholar
  10. 10.
    Dufty BM, Warner LR, Hou ST, Jiang SX, Gomez-Isla T, Leenhouts KM, Oxford JT, Feany MB, Masliah E, Rohn TT (2007) Calpain-cleavage of α-synuclein: connecting proteolytic processing to disease-linked aggregation. Am J Pathol 170:1725–1738PubMedCrossRefGoogle Scholar
  11. 11.
    Fleming SM, Salcedo J, Fernagut P-O, Rockenstein E, Masliah E, Levine MS, Chesselet M-F (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human α-synuclein. J Neurosci 24:9434–9440PubMedCrossRefGoogle Scholar
  12. 12.
    Fleming SM, Salcedo J, Hutson CB, Rockenstein E, Masliah E, Levine MS, Chesselet M-F (2006) Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype α-synuclein. Neuroscience 142:1245–1253PubMedCrossRefGoogle Scholar
  13. 13.
    Freichel C, Neumann M, Ballard T, Müller V, Woolley M, Ozmen L, Borroni E, Kretzschmar HA, Haass C, Spooren W, Kahle PJ (2007) Age-dependent cognitive decline and amygdala pathology in α-synuclein transgenic mice. Neurobiol Aging 28:1421–1435PubMedCrossRefGoogle Scholar
  14. 14.
    Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164PubMedCrossRefGoogle Scholar
  15. 15.
    George JM (2002) The synucleins. Genome Biol 3:REVIEWS3002Google Scholar
  16. 16.
    Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM-Y (2002) Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34:521–533PubMedCrossRefGoogle Scholar
  17. 17.
    Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM-Y (2003) Initiation and synergistic fibrillization of tau and α-synuclein. Science 300:636–640PubMedCrossRefGoogle Scholar
  18. 18.
    Gispert S, Del Turco D, Garrett L, Chen A, Bernard DJ, Hamm-Clement J, Korf H-W, Deller T, Braak H, Auburger G, Nussbaum RL (2003) Transgenic mice expressing mutant A53T human α-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol Cell Neurosci 24:419–429PubMedCrossRefGoogle Scholar
  19. 19.
    Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501PubMedCrossRefGoogle Scholar
  20. 20.
    Gomez-Isla T, Irizarry MC, Mariash A, Cheung B, Soto O, Schrump S, Sondel J, Kotilinek L, Day J, Schwarzschild MA, Cha J-HJ, Newell K, Miller DW, Uéda K, Young AB, Hyman BT, Ashe KH (2003) Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice. Neurobiol Aging 24:245–258PubMedCrossRefGoogle Scholar
  21. 21.
    Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, Axelsen PH, Giasson BI (2005) The E46K mutation in α-synuclein increases amyloid fibril formation. J Biol Chem 280:7800–7807PubMedCrossRefGoogle Scholar
  22. 22.
    Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen S-H, Hardy J, Dickson DW (2000) Distinctive neuropathology revealed by α-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 99:663–672PubMedCrossRefGoogle Scholar
  23. 23.
    Hashimoto M, Rockenstein E, Mante M, Mallory M, Masliah E (2001) β-Synuclein inhibits α-synuclein aggregation. A possible role as an anti-parkinsonian factor. Neuron 32:213–223PubMedCrossRefGoogle Scholar
  24. 24.
    Hishikawa N, Hashizume Y, Yoshida M, Sobue G (2001) Widespread occurrence of argyrophilic glial inclusions in Parkinson’s disease. Neuropathol Appl Neurobiol 27:362–372PubMedCrossRefGoogle Scholar
  25. 25.
    Hoyer W, Cherny D, Subramaniam V, Jovin TM (2004) Impact of the acidic C-terminal region comprising amino acids 109–140 on α-synuclein aggregation in vitro. Biochemistry 43:16233–16242PubMedCrossRefGoogle Scholar
  26. 26.
    Ihara M, Yamasaki N, Hagiwara A, Tanigaki A, Kitano A, Hikawa R, Tomimoto H, Noda M, Takanashi M, Mori H, Hattori N, Miyakawa T, Kinoshita M (2007) Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of α-synuclein neurotoxicity. Neuron 53:519–533PubMedCrossRefGoogle Scholar
  27. 27.
    Kahle PJ, Neumann M, Ozmen L, Müller V, Jacobsen H, Schindzielorz A, Okochi M, Leimer U, van der Putten H, Probst A, Kremmer E, Kretzschmar HA, Haass C (2000) Subcellular localization of wild-type and Parkinson’s disease-associated mutant α-synuclein in human and transgenic mouse brain. J Neurosci 20:6365–6373PubMedGoogle Scholar
  28. 28.
    Kahle PJ, Neumann M, Ozmen L, Müller V, Jacobsen H, Spooren W, Fuss B, Mallon B, Macklin WB, Fujiwara H, Hasegawa M, Iwatsubo T, Kretzschmar HA, Haass C (2002) Hyperphosphorylation and insolubility of α-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3:583–588PubMedCrossRefGoogle Scholar
  29. 29.
    Kahle PJ, Neumann M, Ozmen L, Müller V, Odoy S, Jacobsen H, Iwatsubo T, Trojanowski JQ, Takahashi H, Wakabayashi K, Bogdanovic N, Riederer P, Kretzschmar HA, Haass C (2001) Selective insolubility of α-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 159:2215–2225PubMedGoogle Scholar
  30. 30.
    Klucken J, Ingelsson M, Shin Y, Irizarry MC, Hedley-Whyte ET, Frosch MP, Growdon JH, McLean PJ, Hyman BT (2006) Clinical and biochemical correlates of insoluble α-synuclein in dementia with Lewy bodies. Acta Neuropathol 111:101–108PubMedCrossRefGoogle Scholar
  31. 31.
    Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O (1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet 18:106–108PubMedCrossRefGoogle Scholar
  32. 32.
    Krüger R, Schöls L, Del Tredici K, Seidel K, Braak H, Deller T, Rüb U (2006) Familial Parkinson’s disease: the first pathoanatomical study on a carrier of the A30P mutation in the α-synuclein gene. Movement Disord 21:S610Google Scholar
  33. 33.
    Lantos PL (1998) The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol 57:1099–1111PubMedCrossRefGoogle Scholar
  34. 34.
    Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human α-synuclein-harboring familial Parkinson’s disease-linked Ala-53 -> Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99:8968–8973PubMedCrossRefGoogle Scholar
  35. 35.
    Li W, West N, Colla E, Pletnikova O, Troncoso JC, Marsh L, Dawson TM, Jäkälä P, Hartmann T, Price DL, Lee MK (2005) Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci USA 102:2162–2167PubMedCrossRefGoogle Scholar
  36. 36.
    Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006) Parkinson’s disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26:41–50PubMedCrossRefGoogle Scholar
  37. 37.
    Maskri L, Zhu X, Fritzen S, Kühn K, Ullmer C, Engels P, Andriske M, Stichel CC, Lübbert H (2004) Influence of different promoters on the expression pattern of mutated human α-synuclein in transgenic mice. Neurodegener Dis 1:255–265PubMedCrossRefGoogle Scholar
  38. 38.
    Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, Seubert P, Lee M, Goldstein J, Chilcote T, Games D, Schenk D (2005) Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 46:857–868PubMedCrossRefGoogle Scholar
  39. 39.
    Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269PubMedCrossRefGoogle Scholar
  40. 40.
    Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250PubMedCrossRefGoogle Scholar
  41. 41.
    Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte DA (2001) Lack of nigral pathology in transgenic mice expressing human α-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 8:535–539PubMedCrossRefGoogle Scholar
  42. 42.
    Mishizen-Eberz AJ, Guttmann RP, Giasson BI, Day GA 3rd, Hodara R, Ischiropoulos H, Lee VM-Y, Trojanowski JQ, Lynch DR (2003) Distinct cleavage patterns of normal and pathologic forms of α-synuclein by calpain I in vitro. J Neurochem 86:836–847PubMedCrossRefGoogle Scholar
  43. 43.
    Murray IVJ, Giasson BI, Quinn SM, Koppaka V, Axelsen PH, Ischiropoulos H, Trojanowski JQ, Lee VM-Y (2003) Role of α-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42:8530–8540PubMedCrossRefGoogle Scholar
  44. 44.
    Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Müller V, Odoy S, Fujiwara H, Hasegawa M, Iwatsubo T, Trojanowski JQ, Kretzschmar HA, Haass C (2002) Misfolded proteinase K-resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human α-synucleinopathies. J Clin Invest 110:1429–1439PubMedCrossRefGoogle Scholar
  45. 45.
    Neumann M, Müller V, Kretzschmar HA, Haass C, Kahle PJ (2004) Regional distribution of proteinase K-resistant α-synuclein correlates with Lewy body disease stage. J Neuropathol Exp Neurol 63:1225–1235PubMedGoogle Scholar
  46. 46.
    Nieto M, Gil-Bea FJ, Dalfó E, Cuadrado M, Cabodevilla F, Sánchez B, Catena S, Sesma T, Ribé E, Ferrer I, Ramírez MJ, Gómez-Isla T (2006) Increased sensitivity to MPTP in human α-synuclein A30P transgenic mice. Neurobiol Aging 27:848–856PubMedCrossRefGoogle Scholar
  47. 47.
    Nuscher B, Kamp F, Mehnert T, Odoy S, Haass C, Kahle PJ, Beyer K (2004) α-Synuclein has a high affinity for packing defects in a bilayer membrane: a thermodynamics study. J Biol Chem 279:21966–21975PubMedCrossRefGoogle Scholar
  48. 48.
    Olanow CW, Perl DP, DeMartino GN, McNaught KS (2004) Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 3:496–503PubMedCrossRefGoogle Scholar
  49. 49.
    Park JY, Lansbury PT Jr (2003) β-Synuclein inhibits formation of α-synuclein protofibrils: a possible therapeutic strategy against Parkinson’s disease. Biochemistry 42:3696–3700PubMedCrossRefGoogle Scholar
  50. 50.
    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 α-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  51. 51.
    Rathke-Hartlieb S, Kahle PJ, Neumann M, Ozmen L, Haid S, Okochi M, Haass C, Schulz JB (2001) Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant α-synuclein transgenic mice. J Neurochem 77:1181–1184PubMedCrossRefGoogle Scholar
  52. 52.
    Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ (2002) Behavioral and neurochemical effects of wild-type and mutated human α-synuclein in transgenic mice. Exp Neurol 175:35–48PubMedCrossRefGoogle Scholar
  53. 53.
    Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E (2002) Differential neuropathological alterations in transgenic mice expressing α-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 68:568–578PubMedCrossRefGoogle Scholar
  54. 54.
    Rockenstein E, Schwach G, Ingolic E, Adame A, Crews L, Mante M, Pfragner R, Schreiner E, Windisch M, Masliah E (2005) Lysosomal pathology associated with α-synuclein accumulation in transgenic models using an eGFP fusion protein. J Neurosci Res 80:247–259PubMedCrossRefGoogle Scholar
  55. 55.
    Shults CW, Rockenstein E, Crews L, Adame A, Mante M, Larrea G, Hashimoto M, Song D, Iwatsubo T, Tsuboi K, Masliah E (2005) Neurological and neurodegenerative alterations in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci 25:10689–10699PubMedCrossRefGoogle Scholar
  56. 56.
    Sidhu A, Wersinger C, Vernier P (2004) Does α-synuclein modulate dopaminergic synaptic content and tone at the synapse? FASEB J 18:637–647PubMedCrossRefGoogle Scholar
  57. 57.
    Singleton A, Gwinn-Hardy K (2004) Parkinson’s disease and dementia with Lewy bodies: a difference in dose?. Lancet 364:1105–1107PubMedCrossRefGoogle Scholar
  58. 58.
    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 302:841PubMedCrossRefGoogle Scholar
  59. 59.
    Specht CG, Schoepfer R (2004) Deletion of multimerin-1 α-synuclein-deficient mice. Genomics 83:1176–1178PubMedCrossRefGoogle Scholar
  60. 60.
    Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208PubMedCrossRefGoogle Scholar
  61. 61.
    Spillantini MG, Schmidt ML, Lee VM-Y, Trojanowski JQ, Jakes R, Goedert M (1997) α-Synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  62. 62.
    Spira PJ, Sharpe DM, Halliday G, Cavanagh J, Nicholson GA (2001) Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr α-synuclein mutation. Ann Neurol 49:313–319PubMedCrossRefGoogle Scholar
  63. 63.
    Stefanova N, Reindl M, Neumann M, Haass C, Poewe W, Kahle PJ, Wenning GK (2005) Oxidative stress in transgenic mice with oligodendroglial α-Synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol 166:869–876PubMedGoogle Scholar
  64. 64.
    Stefanova N, Reindl M, Neumann M, Kahle PJ, Poewe W, Wenning GK (2007) Microglial activation mediates neurodegeneration related to oligodendroglial α-synucleinopathy: implications for multiple system atrophy. Movement Disord.  doi:10.1002/mds.21671
  65. 65.
    Steidl JV, Gomez-Isla T, Mariash A, Hsiao Ashe K, Boland LM (2003) Altered short-term hippocampal synaptic plasticity in mutant α-synuclein transgenic mice. NeuroReport 14:219–223PubMedCrossRefGoogle Scholar
  66. 66.
    Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK (2004) Risk factors for dopaminergic neuron loss in human α-synuclein transgenic mice. Eur J Neurosci 19:845–854PubMedCrossRefGoogle Scholar
  67. 67.
    Tofaris GK, Garcia Reitböck P, Humby T, Lambourne SL, O’Connell M, Ghetti B, Gossage H, Emson PC, Wilkinson LS, Goedert M, Spillantini MG (2006) Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human α-synuclein(1–120): implications for Lewy body disorders. J Neurosci 26:3942–3950PubMedCrossRefGoogle Scholar
  68. 68.
    Touchman JW, Dehejia A, Chiba-Falek O, Cabin DE, Schwartz JR, Orrison BM, Polymeropoulos MH, Nussbaum RL (2001) Human and mouse α-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element. Genome Res 11:78–86PubMedCrossRefGoogle Scholar
  69. 69.
    Unger EL, Eve DJ, Perez XA, Reichenbach DK, Xu Y, Lee MK, Andrews AM (2006) Locomotor hyperactivity and alterations in dopamine neurotransmission are associated with overexpression of A53T mutant human α-synuclein in mice. Neurobiol Dis 21:431–443PubMedCrossRefGoogle Scholar
  70. 70.
    Uversky VN, Li J, Souillac P, Millett IS, Doniach S, Jakes R, Goedert M, Fink AL (2002) Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of α-synuclein assembly by β- and γ-synucleins. J Biol Chem 277:11970–11978PubMedCrossRefGoogle Scholar
  71. 71.
    Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90:11282–11286PubMedCrossRefGoogle Scholar
  72. 72.
    van der Putten H, Wiederhold K-H, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WPJM, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G (2000) Neuropathology in mice expressing human α-synuclein. J Neurosci 20:6021–6029PubMedGoogle Scholar
  73. 73.
    von Coelln R, Thomas B, Andrabi SA, Lim KL, Savitt JM, Saffary R, Stirling W, Bruno K, Hess EJ, Lee MK, Dawson VL, Dawson TM (2006) Inclusion body formation and neurodegeneration are parkin independent in a mouse model of α-synucleinopathy. J Neurosci 26:3685–3696CrossRefGoogle Scholar
  74. 74.
    Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, Yoshimoto M, Takahashi H (1998) Accumulation of α-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol 96:445–452PubMedCrossRefGoogle Scholar
  75. 75.
    Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/α-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 99:14–20PubMedCrossRefGoogle Scholar
  76. 76.
    Wakamatsu M, Ishii A, Iwata S, Sakagami J, Ukai Y, Ono M, Kanbe D, Muramatsu S, Kobayashi K, Iwatsubo T, Yoshimoto M (2006) Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice. Neurobiol Aging.  doi:10.1016/j.neurobiolaging.2006.11.017
  77. 77.
    Winner B, Lie DC, Rockenstein E, Aigner R, Aigner L, Masliah E, Kuhn HG, Winkler J (2004) Human wild-type α-synuclein impairs neurogenesis. J Neuropathol Exp Neurol 63:1155–1166PubMedGoogle Scholar
  78. 78.
    Winner B, Rockenstein E, Lie DC, Aigner R, Mante M, Bogdahn U, Couillard-Depres S, Masliah E, Winkler J (2007) Mutant α-synuclein exacerbates age-related decrease of neurogenesis. Neurobiol Aging.  doi:10.1016/j.neurobiolaging 2006.12.016
  79. 79.
    Yamaguchi K, Cochran EJ, Murrell JR, Polymeropoulos MH, Shannon KM, Crowther RA, Goedert M, Ghetti B (2005) Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene. Acta Neuropathol 110:298–305PubMedCrossRefGoogle Scholar
  80. 80.
    Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, Trojanowski JQ, Lee VM-Y (2005) Mouse model of multiple system atrophy: α-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45:847–859PubMedCrossRefGoogle Scholar
  81. 81.
    Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz DG, de Yebenes JG (2004) The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie-Institute for Clinical Brain ResearchUniversity Clinics TübingenTübingenGermany

Personalised recommendations