Acta Neuropathologica

, Volume 114, Issue 5, pp 481–489 | Cite as

Neuronal and glial accumulation of α- and β-synucleins in human lipidoses

  • Kyoko Suzuki
  • Eizo Iseki
  • Takashi Togo
  • Akira Yamaguchi
  • Omi Katsuse
  • Kayoko Katsuyama
  • Seiichi Kanzaki
  • Kazumasa Shiozaki
  • Chiaki Kawanishi
  • Sumimasa Yamashita
  • Yukichi Tanaka
  • Shoji Yamanaka
  • Yoshio Hirayasu
Original Paper

Abstract

A number of the lysosomal storage diseases that have now been characterized are associated with intra-lysosomal accumulation of lipids, caused by defective lysosomal enzymes. We have previously reported neuronal accumulation of both α- and β-synucleins in brain tissue of a GM2 gangliosidosis mouse model. Although α-synuclein has been implicated in several neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, its functions remain largely unclear. In our present study, we have examined a cohort of human lipidosis cases, including Sandhoff disease, Tay–Sachs disease, metachromatic leukodystrophy, β-galactosialidosis and adrenoleukodystrophy, for the expression of α- and β-synucleins and the associated lipid storage levels. The accumulation of α-synuclein was found in brain tissue in not only cases of lysosomal storage diseases, but also in instances of adrenoleukodystrophy, which is a peroxisomal disease. α-synuclein was detected in both neurons and glial cells of patients with these two disorders, although its distribution was found to be disease-dependent. In addition, α-synuclein-positive neurons were also found to be NeuN-positive, whereas NeuN-negative neurons did not show any accumulation of this protein. By comparison, the accumulation of β-synuclein was detectable only in the pons of Sandhoff disease cases. This differential accumulation of α- and β-synucleins in human lipidoses may be related to functional differences between these two proteins. In addition, the accumulation of α-synuclein may also be a condition that is common to lysosomal storage diseases and adrenoleukodystrophies that show an enhanced expression of this protein upon the elevation of stored lipids.

Keywords

α-synuclein Lysosome Peroxisome Lipid storage Neuronal nuclei 

References

  1. 1.
    Amano N, Yokoi S, Akagi M, Sakai M, Yagishita S, Nakata K (1983) Neuropathological findings of an autopsy case of adult β-galactosidase and neuraminidase deficiency. Acta Neuropathol 61:283–290PubMedCrossRefGoogle Scholar
  2. 2.
    Arawaka S, Saito Y, Murayama S, Mori H (1998) Lewy body is neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein. Neurology 51:887–889PubMedGoogle Scholar
  3. 3.
    Brenz Verca M, Bahi A, Boyer F, Wagner GC, Dreyer JL (2003) Distribution of α- and γ-synucleins in the adult rat brain and their modification by high-dose cocaine treatment. Eur J Neurosci 18:1923–1938PubMedCrossRefGoogle Scholar
  4. 4.
    Croisier E, Graeber MB (2006) Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration. Acta Neuropathol 112:517–530PubMedCrossRefGoogle Scholar
  5. 5.
    Elleder M, Sokolova J, Hrebicek M (1997) Follow-up study of subunit c mitochondrial ATP synthase (SCMAS) in Batten disease and in unrelated lysosomal; disorders. Acta Neuropathol 93:379–390PubMedCrossRefGoogle Scholar
  6. 6.
    Futerman AH, Meer GV (2004) The cell biology of lysosomal storage disorders. Nat Rev 5:554–565CrossRefGoogle Scholar
  7. 7.
    Goebel HH, Lake BD (1998) Lysosomal and peroxisomal disorders. Recent advances introduction. Brain Pathol 8:73–78PubMedCrossRefGoogle Scholar
  8. 8.
    Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev 2:492–501CrossRefGoogle Scholar
  9. 9.
    Haik S, Privat N, Adjou KT, Sazdovitch V, Dormont D, Duyckaerts C, Hauw JJ (2002) Alpha-synuclein-immunoreactive deposits in human and animal prion diseases. Acta Neuropathol 103:516–520PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    Katsuragi T, Iseki E, Kosaka K, Nishimura T, Akiyama H, Ikeda K, Kato M (1996) Immunohistochemical investigation of human leukocyte antigen (HLA)-DR-positive astrocytes in adrenoleukodystrophy brain. Neurosci Lett 219:207–210PubMedCrossRefGoogle Scholar
  12. 12.
    Katsuse O, Iseki E, Suzuki K, Kosaka K (2001) Frequency and distribution of TUNEL-positive neurons in brains of dementia with Lewy bodies. Comparison with those in brains of Alzheimer’s disease. Neuropathology 21:272–277PubMedCrossRefGoogle Scholar
  13. 13.
    Kumar SS, Buckmaster PS (2007) Neuron-specific nuclear antigen NeuN is not detectable in gerbil subtantia nigra pars reticulata. Brain Res 1142:54–60PubMedCrossRefGoogle Scholar
  14. 14.
    Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, Nee LE, O’Connell B, Pollen DA, St George-Hyslop P, Ghetti B, Nochlin D, Bind TD, Cairns NJ, Lee VM, Iwatsubo T, Trojanowski JQ (1998) Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol 153:1365–1370PubMedGoogle Scholar
  15. 15.
    Martinez Z, Zhu M, Han S, Fink AL (2007) GM1 Specifically interacts with α-synuclein and inhibits fibrillation. Biochemistry 46:1868–1877PubMedCrossRefGoogle Scholar
  16. 16.
    Marui W, Iseki E, Ueda K, Kosaka K (2000) Occurrence of human α-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer’s disease. J Neurol Sci 174:81–84PubMedCrossRefGoogle Scholar
  17. 17.
    Marui W, Iseki E, Nakai T, Miura S, Kato M, Ueda K, Kosaka K (2002) Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies. J Neurol Sci 195:153–159PubMedCrossRefGoogle Scholar
  18. 18.
    Matsuzaki M, Hasegawa T, Takeda A, Kikuchi A, Furukawa K, Kato Y, Itoyama Y (2004) Histochemical features of stress-induces aggregates in(α-synuclein overexpressing cells. Brain Res 1004:83–90PubMedCrossRefGoogle Scholar
  19. 19.
    Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated α-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654PubMedGoogle Scholar
  20. 20.
    Saito Y, Suzuki K, Hulette CM, Murayama S (2004) Aberrant phosphorylation of α-synuclein in human Niemann–Pick type C1 disease. J Neuropathol Exp Neurol 63:323–328PubMedGoogle Scholar
  21. 21.
    Sharon R, Bar-Jaseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ (2003) The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 37:583–595PubMedCrossRefGoogle Scholar
  22. 22.
    Sidhu A, Wersinger C, Moussa CEH, Vernier P (2004) The role of α-synuclein in both neuroprotection and neurodegeneration. Ann NY Acad Sci 1035:250–270PubMedCrossRefGoogle Scholar
  23. 23.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  24. 24.
    Suzuki K, Yokoi S, Iseki E, Yamada Y, Arai N, Matsushita M (1990) Changes of glycolipids in the human brain after formalin fixation. J Clin Chem Jpn 19:131–135Google Scholar
  25. 25.
    Suzuki K, Iseki E, Katsuse O, Yamaguchi A, Katsuyama K, Yamanaka S, Kosaka K (2003) Neuronal accumulation of α- and β-synucleins in the brain of a GM2 gangliosidosis mouse model. Neuroreport 14:551–554PubMedCrossRefGoogle Scholar
  26. 26.
    Takeda A, Hasegawa T, Matsuzaki-Kobayashi M, Sugeno N, Kikuchi A, Itoyama Y, Furukawa K (2006) Mechanisms of neuronal death in synucleinopathy. J Biomed Biotechnol 2006:1–4CrossRefGoogle Scholar
  27. 27.
    Tatematsu M, Imaida K, Ito N, Togari H, Suzuki Y, Ogiu T (1981) Sandhoff disease. Acta Pathol Jpn 31:503–512PubMedGoogle Scholar
  28. 28.
    Tu PH, Galvin JE, Baba M (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44:415–422PubMedCrossRefGoogle Scholar
  29. 29.
    Ueda K, Fukushima H, Musliah 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
  30. 30.
    Wenning GK, Jellinger KA (2005) The role of α-synuclein in the pathogenesis of multiple system atrophy. Acta Neuropathol 109:129–140PubMedCrossRefGoogle Scholar
  31. 31.
    Wong K, Sidransky E, Verma A, Mixon T, Sandberg GD, Wakefield LK, Morrison A, Lwin A, Colegial C, Allman JM, Schiffmann R (2004) Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 82:192–207PubMedCrossRefGoogle Scholar
  32. 32.
    Yamaguchi A, Katsuyama K, Nagahama K, Takai T, Aoki I, Yamanaka S (2004) Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses. J Clin Invest 113: 200–208PubMedCrossRefGoogle Scholar
  33. 33.
    Yokoi S (1967) Lipidosis—with special reference to metachromatic leukodystrophy and Tay–Sachs disease. Nippon Rinsho Jpn 25:1597–1606Google Scholar
  34. 34.
    Zhan SS, Beyreuther K, Schmitt HP (1992) Neuronal ubiquitin and neurofilament expression in different lysosomal storage disorders. Clinical Neuropathol 11:251–255Google Scholar
  35. 35.
    Zhu M, Fink AL (2003) Lipid binding inhibits α-synuclein fibril formation. J Biol Chem 278:16873–16877PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Kyoko Suzuki
    • 1
  • Eizo Iseki
    • 2
  • Takashi Togo
    • 1
  • Akira Yamaguchi
    • 3
  • Omi Katsuse
    • 1
  • Kayoko Katsuyama
    • 3
  • Seiichi Kanzaki
    • 3
  • Kazumasa Shiozaki
    • 1
  • Chiaki Kawanishi
    • 1
  • Sumimasa Yamashita
    • 4
  • Yukichi Tanaka
    • 4
  • Shoji Yamanaka
    • 3
  • Yoshio Hirayasu
    • 1
  1. 1.Department of PsychiatryYokohama City University School of MedicineYokohamaJapan
  2. 2.Juntendo Tokyo Koto Geriatric Medical CenterJuntendo University School of MedicineTokyoJapan
  3. 3.Department of PathologyYokohama City University School of MedicineYokohamaJapan
  4. 4.Division of Neurology, PathologyKanagawa Children’s Medical CenterYokohamaJapan

Personalised recommendations