Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;9(4):721–732. doi: 10.1111/j.1750-3639.1999.tb00553.x

Multiple System Atrophy: A Sporadic Synucleinopathy

Dennis W Dickson 1,✉, Wen‐lang Lin 1, Wan‐Kyun Liu 2, Shu‐Hui Yen 2
PMCID: PMC8098455  PMID: 10517510

Abstract

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease characterized clinically by varying degrees of Parkinsonism, cerebellar ataxia and autonomic dysfunction and pathologically by degeneration in the substantia nigra, putamen, olivary nucleus, pontine nuclei and cerebellum. In addition to selective neuronal loss, iron pigment accumulation and gliosis, myelin pathology is increasingly recognized. In affected white matter, myelin displays signs of degeneration and oligodendroglia contain argyrophilic inclusion bodies, so‐called glial cytoplasmic inclusions (GCI). GCI are composed of 10–15‐nm diameter coated filaments that are immunoreactive for ubiquitin and α‐synuclein. Similar inclusions are occasionally found in neuronal cell bodies and cell processes in MSA. Given the presence of inclusion bodies composed of synuclein, it is reasonable to assume that biochemical alterations would be detected in synuclein in MSA and indeed this is the case. In MSA synuclein has biophysical properties that suggest increasing insolubility such as sedimentation in dense fractions in sucrose gradients and ready extraction into detergents and formic acid. Surprisingly, these biochemical modifications in synuclein are more widespread in the brain that the obvious pathology and suggest a fundamental molecular characteristic of the disorder. Similar neuronal, and less frequently glial, inclusions are detected in Lewy body disease, where there is also evidence for biophysical alterations in synuclein. Thus, MSA and LBD are both synucleinopathies, and they may comprise different poles of a disease spectrum that includes sporadic disorders as well as genetically determined disorders such as familial Lewy body Parkinsonism.

Full Text

The Full Text of this article is available as a PDF (600.6 KB).

References

  • 1. Arai N, Papp MI, Lantos PL (1994) New observation on ubiquitinated neurons in the cerebral cortex of multiple system atrophy (MSA). Neurosci Lett 182: 197–200. [DOI] [PubMed] [Google Scholar]
  • 2. Arima K, Murayama S, Mukoyama M, Inose T (1992) Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. 1 Neuronal cytoplasmic inclusions. Acta Neuropathol 83: 453–460. [DOI] [PubMed] [Google Scholar]
  • 3. Arima K, Nakamura M, Sunohara N, Ogawa M, Anno M, Izumiyama, Y Hirai S, Ikeda K (1997) Ultrastructural characterization of the tau‐immunoreactive tubules in the oligodendroglial perikarya and their inner loop processes in progressive supranuclear palsy. Acta Neuropathol 93: 558–566. [DOI] [PubMed] [Google Scholar]
  • 4. Arima K, Ueda 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: 439–444. [DOI] [PubMed] [Google Scholar]
  • 5. Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alphasynuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol 152: 879–884. [PMC free article] [PubMed] [Google Scholar]
  • 6. Bandmann O, Sweeney MG, Daniel SE, Wenning GK, Quinn N, Marsden CD, Wood NW (1997) Multiple‐system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration. Neurology 49: 1598–1604. [DOI] [PubMed] [Google Scholar]
  • 7. Beal MF (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta 1366:211–223. [DOI] [PubMed] [Google Scholar]
  • 8. Bower JH, Maraganore DM, McDonnell SK, Rocca WA (1997) Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 49: 1284–1248. [DOI] [PubMed] [Google Scholar]
  • 9. Braak H, Braak E (1989) Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol Appl Neurobiol 15: 13–26. [DOI] [PubMed] [Google Scholar]
  • 10. Cairns NJ, Atkinson PF, Hanger DP, Anderton BH, Daniel SE, Lantos PL (1997) Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer's disease. Neurosci Lett 230: 49–52. [DOI] [PubMed] [Google Scholar]
  • 11. Castellani R (1998) Multiple system atrophy: clues from inclusions. Am J Pathol 153: 671–676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Cervos‐Navarro J, Urich H (1995) Degenerative disease of the cerebellum, brainstem and spinal cord (spinocerebellar degenerations). Metabolic and Degenerative Diseases of The Central Nervous System: Pathology, Biochemistry and Genetics. San Diego , Academic Press; pp. 573–624. [Google Scholar]
  • 13. Chin SSM, Goldman JE (1996) Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol 55: 499–508. [DOI] [PubMed] [Google Scholar]
  • 14. Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant α‐synuclein linked to early‐onset Parkinson disease. Nature Med 4:1318–1320. [DOI] [PubMed] [Google Scholar]
  • 15. Crowther RA, Jakes R, Spillantini MG, Goedert M (1998) Synthetic filaments assembled from C‐terminally truncated alpha‐synuclein. FEBS Lett 436: 309–312. [DOI] [PubMed] [Google Scholar]
  • 16. Davies SW, Beardsall K, Turmaine M, DiFigurelia M, Aronin N, Bates GP (1998) Are neuronal intranuclear inclusions the common neuropathology of triplet‐repeat disorders with polyglutamine‐repeat expansions Lancet 351: 131–133. [DOI] [PubMed] [Google Scholar]
  • 17. Delacourte A, Buee L (1997) Normal and pathological Tau proteins as factors for microtubule assembly. Int Rev Cytol 171:167–224. [DOI] [PubMed] [Google Scholar]
  • 18. Dexter DT, Carayon A, Javoy‐Agid F, Agid Y, Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114: 1953–1975. [DOI] [PubMed] [Google Scholar]
  • 19. Dickson DW, Farrer MJ, Mehta ND, Perez‐Tur J, Tiseo P, Yen S‐H, Hardy J (1998) Antibodies to non‐amyloid component of plaques (NACP) specifically label Lewy bodies and Lewy neurites, but not other inclusions in neurodegenerative diseases (Abstr). J Neuropathol Exp Neurol 57: 516. [Google Scholar]
  • 20. Dickson DW, Liu W‐K, Farrer M, Mehta N, Uitti R, Mark M, Zimmerman T, Golbe L, Sage J, Hardy J, Yen S‐H (1998) Glial cytoplasmic inclusions (GCI) of multiple system atrophy (MSA) contain alpha‐synuclein (Abstr). Movement Dis 13(Suppl2): 128. [Google Scholar]
  • 21. Dickson DW, Liu W‐K, Hardy J, Farrer M, Mehta N, Uitti R, Mark M, Zimmerman T, Golbe L, Sage J, Sima A, D'Amato C, Albin R, Gilman S, Yen S‐H. (1999) Widespread alterations of alpha‐synuclein in multiple system atrophy. Am J Pathol (in Press). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Dickson DW, Ruan D, Crystal H, Mark MH, Davies P, Kress Y, Yen S‐H (1991) Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: light and electron microscopic immunocytochemistry of CA2‐3 neurites specific to DLBD. Neurology 41: 1402–1409. [DOI] [PubMed] [Google Scholar]
  • 23. Dickson DW, Yen SH, Suzuki KI, Davies P, Garcia JH, Hirano A (1986) Ballooned neurons in select neurodegenerative diseases contain phosphorylated neurofilament epitopes. Acta Neuropathol 71: 216–223. [DOI] [PubMed] [Google Scholar]
  • 24. van der Eecken H, Adams RD, van Bogaert L (1960) Striatopallido‐nigral degeneration. An hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 19: 159–164. [Google Scholar]
  • 25. EI‐Agnaf OM, Jakes R, Curran MD, Wallace A (1998) Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha‐synuclein protein implicated in Parkinson's disease. FEBS Lett 440: 67–70. [DOI] [PubMed] [Google Scholar]
  • 26. Gai WP, Power JH, Blumbergs PC, Blessing WW (1998) Multiple‐system atrophy: a new alpha‐synuclein disease Lancet 352: 547–548. [DOI] [PubMed] [Google Scholar]
  • 27. 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: 7619–7622. [DOI] [PubMed] [Google Scholar]
  • 28. Gilman S, Low PA, Quinn N, Albanese A, Ben‐Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK (1998) Consensus statement on the diagnosis of multiple system atrophy. J Autonomie Nerv System 74: 189–192. [PubMed] [Google Scholar]
  • 29. Gilman S, Quinn NP (1996) The relationship of multiple system atrophy to sporadic olivopontocerebellar atrophy and other forms of idiopathic late‐onset cerebellar atrophy. Neurology 46: 1197–1199. [DOI] [PubMed] [Google Scholar]
  • 30. Golbe LI (1993) Progressive supranuclear palsy In: Stern MB, Koller WC (eds) Parkinsonian Syndromes. New York , Marcel Dekker; pp. 227–247. [Google Scholar]
  • 31. Graham JG, Oppenheimer DR (1969) Orthostatic hypertension and nicotine insensitivity in a case of multiple system atrophy. J Neurol Neurosurg 32: 28–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Gwinn‐Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Hardy J, Dickson DW (1999) Distinctive neuropathology revealed by a‐synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. (submitted). [DOI] [PubMed]
  • 33. Hardy J, Gwinn‐Hardy K (1998) Genetic classification of primary neurodegenerative disease. Science 282: 1075–1078. [DOI] [PubMed] [Google Scholar]
  • 34. Hashimoto M, Hsu LJ, Sisk A, Xia Y, Takeda A, Sundsmo M, Masliah E (1998) Human recombinant NACP/alpha‐synuclein is aggregated and fibrillated in vitro: relevance for Lewy body disease. Brain Res 799: 301–306. [DOI] [PubMed] [Google Scholar]
  • 35. Horoupian DS, Dickson DW (1991) Striatonigral degeneration, olivopontocerebellar atrophy and “atypical” Pick disease. Acta Neuropathol 81: 287–295. [DOI] [PubMed] [Google Scholar]
  • 36. Inoue M, Yagishita S, Ryo M, Hasegawa K, Amano N, Matsushita M (1997) The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems. Acta Neuropathol 93: 585–591. [DOI] [PubMed] [Google Scholar]
  • 37. Irizarry MC, Growdon W, Gomez‐Isla T, Newell K, George JM, Clayton DF, Hyman BT (1998) Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha‐synuclein immunoreactivity. J Neuropathol Exp Neurol 57: 334–337. [DOI] [PubMed] [Google Scholar]
  • 38. Irizarry MC, Kim T‐W, McNamara M, Tanzi RE, George JM, Clayton DF, Hyman BT (1996) Characterization of the precursor protein of the non‐Aβ component of senile plaques (NACP) in the human central nervous system. J Neuropathol Exp Neurol 55: 889–895. [DOI] [PubMed] [Google Scholar]
  • 39. Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, De Silva HA, Kittel A, Saitoh T (1995) The precursor protein of non‐Aβ component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron 14: 467–475. [DOI] [PubMed] [Google Scholar]
  • 40. Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synuclein from human brain. FEBS Lett 345: 27–32. [DOI] [PubMed] [Google Scholar]
  • 41. Kato S, Meshitsuka S, Ohama E, Tanaka J, Llena JF, Hirano A (1992) Increased iron content in the putamen of patients with striatonigral degeneration. Acta Neuropathol 84: 328–330. [DOI] [PubMed] [Google Scholar]
  • 42. Kato S, Nakamura H, Hirano A, Ito H, Llena JF, Yen SH (1991) Argyrophilic ubiquitinated cytoplasmic inclusions of Leu‐7‐positive glial cells in olivopontocerebellar atrophy (multiple system atrophy). Acta Neuropathol 82: 488–493. [DOI] [PubMed] [Google Scholar]
  • 43. Kato S, Nakamura H (1990) Cytoplasmic argyrophilic inclusions in neurons of pontine nuclei in patients with olivopontocerebellar atrophy: immunohistochemical and ultrastructural studies. Acta Neuropathol 79: 584–594. [DOI] [PubMed] [Google Scholar]
  • 44. Koeppen AH (1998) The hereditary ataxias. J Neuropathol Exp Neurol 57: 531–543. [DOI] [PubMed] [Google Scholar]
  • 45. Koike Y, Takahashi A (1997) Autonomic dysfunction in Parkinson's disease. Eur Neurol 38(Suppl 2): 8–12. [DOI] [PubMed] [Google Scholar]
  • 46. Koshy BT, Zoghbi HY (1997)The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. Brain Pathol 7: 927–942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Reiss O (1998) Ala‐30‐Pro mutation in the gene encoding a‐synuclein in Parkinson's disease. Nature Gen 18: 106–108. [DOI] [PubMed] [Google Scholar]
  • 48. Lang AE, Curran T, Provias J, Bergeron C (1994) Striatonigral degeneration: Deposition in putamen correlates with the slit‐like void signal of magnetic resonance imaging. Can J Neurol Sci 21: 311–318. [DOI] [PubMed] [Google Scholar]
  • 49. Lantos PL (1998) The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol 57: 1099–1111. [DOI] [PubMed] [Google Scholar]
  • 50. Lee VM‐Y, Trojanowski JQ (1995) Tau proteins and their significance in the pathobiology of Alzheimer's disease In: Goate AM, Ashall F (eds) Neuroscience Perspectives: Neurofibrillary Tangles and Amyloid Precursor Protein in Alzheimer's Disease. New York , Academic Press; pp. 41–58. [Google Scholar]
  • 51. Liu W‐K, Ksiezak‐Reding H, Yen S‐H (1991) Abnormal tau proteins from Alzheimer's brains: Purification and amino acid analysis. J Biol Chem 266: 21723–21727. [PubMed] [Google Scholar]
  • 52. Martin WR, Roberts TE, Ye FQ, Allen PS (1998) Increased basal ganglia iron in striatonigral degeneration: in vivo estimation with magnetic resonance. Can J Neurol Sci 25:44–47, 1998. [DOI] [PubMed] [Google Scholar]
  • 53. Matsuo A, Akiguchi I, Lee GC, McGeer EG, McGeer PL, Kimura J (1998) Myelin degeneration in multiple system atrophy detected by unique antibodies. Am J Pathol 153: 735–744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Mezey E, Dehejia A, Harta G, Papp Ml, Polymeropoulos MH, Brownstein MJ (1998) Alpha synuclein in neurodegenerative disorders: murderer or accomplice Nature Med 4: 755–757. [DOI] [PubMed] [Google Scholar]
  • 55. Mizusawa H, Matsumoto S, Yen SH, Hirano A, Rojas‐Corona RR, Donnenfeld H (1989) Focal accumulation of phosphorylated neurofilaments within anterior horn cell in familial amyotrophic lateral sclerosis. Acta Neuropathol 79: 37–43. [DOI] [PubMed] [Google Scholar]
  • 56. Nakamura S, Kawamoto Y, Nakano S, Akiguchi I, Kimura J (1998) Cyclin‐dependent kinase 5 and mitogen‐activated protein kinase in glial cytoplasmic inclusions in multiple system atrophy. J Neuropathol Exp Neurol 57: 690–698. [DOI] [PubMed] [Google Scholar]
  • 57. Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron M (1999) Both familial Parkinson's disease mutations accelerate alpha‐synuclein aggregation. J Biol Chem 274: 9843–9846. [DOI] [PubMed] [Google Scholar]
  • 58. Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy‐Drager syndrome). J Neurol Sci 94: 79–100. [DOI] [PubMed] [Google Scholar]
  • 59. Papp MI, Lantos PL (1994) The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 117: 235–243. [DOI] [PubMed] [Google Scholar]
  • 60. Parati EA, Fetoni V, Geminiani GC, Soliveri P, Giovannini P, Testa D, Genitrini S, Caraceni T, Girotti F (1993) Response to L‐DOPA in multiple system atrophy. Clin Neuropharmacol 16: 139–144. [DOI] [PubMed] [Google Scholar]
  • 61. Polymeropoulos MHC, 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. [DOI] [PubMed] [Google Scholar]
  • 62. Robitaille Y, Lopes‐Cendes I, Becher M, Rouleau G, Clark AW (1997)The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 7: 901–926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95: 55–66. [DOI] [PubMed] [Google Scholar]
  • 64. Sayre LM, Perry G, Smith MA (1999) Redox metals and neurodegenerative disease. Curr Opin Chem Biol 3: 220–225. [DOI] [PubMed] [Google Scholar]
  • 65. Schwarz J, Weis S, Kraft E, Tatsch K, Bandmann O, Mehraein P, Vogl T, Oertel WH (1996) Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 60: 98–101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Shy GM, Drager GA (1960)A neurological syndrome associated with orthostatic hypotension: a clinicopatho‐logic study. Arch Neurol 2: 511–527. [DOI] [PubMed] [Google Scholar]
  • 67. 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: 205–208. [DOI] [PubMed] [Google Scholar]
  • 68. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) a‐Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci (USA) 95: 6469–6473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha‐synuclein in Lewy bodies. Nature 388: 839–840. [DOI] [PubMed] [Google Scholar]
  • 70. Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E (1998) Abnormal accumulation of NACP/α‐synuclein in neurodegenerative disorders. Am J Pathol 152:367–372. [PMC free article] [PubMed] [Google Scholar]
  • 71. Tamaoka A, Mizusawa H, Mori H, Shoji S (1995). Ubiquitinated alpha B‐crystallin in glial cytoplasmic inclusions from the brain of a patient with multiple system atrophy. J Neurol Sci 129: 192–198. [DOI] [PubMed] [Google Scholar]
  • 72. Tu P‐h, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee V M‐Y (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α‐synuclein. Ann Neurol 44: 415–422. [DOI] [PubMed] [Google Scholar]
  • 73. Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DAC, 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: 11282–11286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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: 445–452. [DOI] [PubMed] [Google Scholar]
  • 75. Wakabayashi K, Matsumoto K, Takayama K, Yoshimoto M, Takahashi H (1997) NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease. Neurosci Lett 239: 45–48. [DOI] [PubMed] [Google Scholar]
  • 76. Wakabayashi K, Takahashi H (1997). Neuropathology of autonomie nervous system in Parkinson's disease. Eur Neurol 38(Suppl 2): 2–7. [DOI] [PubMed] [Google Scholar]
  • 77. Wakabayashi K, Takahashi H (1996) Gallyas‐positive, tau‐negative glial inclusions in Parkinson's disease midbrain. Neurosci Lett 217:133–136. [PubMed] [Google Scholar]
  • 78. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha‐synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249: 180–182. [DOI] [PubMed] [Google Scholar]
  • 79. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT Jr (1996) NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 35: 13709–13715. [DOI] [PubMed] [Google Scholar]
  • 80. Wenning GK, Quinn NP (1997) Parkinsonism: Multiple system atrophy. Baillieres Clin Neurol 6: 187–204. [PubMed] [Google Scholar]
  • 81. Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP (1997) Multiple system atrophy: a review of 203 pathologically proven cases. Movement Dis 12: 133–147. [DOI] [PubMed] [Google Scholar]
  • 82. Yamada T, McGeer PL (1990) Oligodendroglial micro‐tubular masses: an abnormality observed in some human neurodegenerative diseases. Neurosci Lett 120: 163–166. [DOI] [PubMed] [Google Scholar]
  • 83. Yen SH, Kress Y (1983) The effect of chemical reagents or proteases on the ultrastructure of paired helical filaments In: Katzman R (ed) Biological Aspects of Alzheimer's Disease. Cold Spring Harbor , NY , Cold Spring Harbor Laboratory; pp. 155–164. [Google Scholar]
  • 84. Yen S‐H, Liu W‐K, Hall FL, Yan S‐D, Stern D, Dickson DW (1995) Alzheimer neurofibrillary lesions: molecular nature and potential roles of different components. Neurobiol Aging 16:381–387. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES