Skip to main content
NCBI home page
Elsevier - PMC COVID-19 Collection logoLink to Elsevier - PMC COVID-19 Collection
. 1999 Mar 26;2(3):113–121. doi: 10.1016/1353-8020(96)00006-5

Viral etiology of Parkinson's disease: Focus on influenza A virus

Tatsuo Yamada ∗
PMCID: PMC7128656  PMID: 18591027

Abstract

Some clinical reports and epidemiological data suggest that a virus may play a role in the etiology of Parkinson's disease (PD). Following intracerebral injection of a neurovirululent strain of influenza A virus into mice, the virus was found to be particularly localized in neurons of the substantia nigra and hippocampus. Although efforts to detect virus particles in the brains, or antibodies in the serum or CSF of patients with PD have been generally unsuccessful, recent immunohistochemical work has revealed the presence of complement proteins and the interferon-induced MxA in association with Lewy bodies and swollen neuronal processes. Although a viral etiology for PD is not now widely accepted, we proposed such an hypothesis. Neurovirulent influenza A virus is a candidate, but some other viruses or complex infection of these viruses may be responsible for the formation of Lewy bodies and the later death of nigral neurons.

Keywords: Parkinson's disease, Influenza A virus, Complement protein, Factor Xa

References

  • 1.Hudson AJ, Rice GPA. Similarities of Guamanian ALS/PD to post-encephalitic parkinsonism/ALS: possible viral cause. Can. J. Neurol. Sci. 1990;17:427–433. doi: 10.1017/s0317167100031024. [DOI] [PubMed] [Google Scholar]
  • 2.Shoji H, Watanabe M, Itoh S, Kuwahara H, Hattori F. Japanese encephalitis and parkinsonism. J. Neurology. 1993;240:59–60. doi: 10.1007/BF00838449. [DOI] [PubMed] [Google Scholar]
  • 3.Walters JH. Postencephalitic Parkinson syndrome after meningoencephalitis due to coxackie virus group B, type 2. New Engl. J. Med. 1960;263:744–747. [Google Scholar]
  • 4.Mulder DW, Parrot M, Thaler M. Sequelae of western equine encephalitis. Neurology. 1951;1:318–327. doi: 10.1212/wnl.1.7-8.318. [DOI] [PubMed] [Google Scholar]
  • 5.Isgreen WP, Chutorian AM, Fahn S. Sequential parkinsonism and chorea following ‘mild’ influenza. Trans. Am. Neurol. Assoc. 1976;101:56–59. [PubMed] [Google Scholar]
  • 6.Solbrig MV. Acute parkinsonism in suspected herpes simplex encephalitis. Mov. Disord. 1993;8:233–234. doi: 10.1002/mds.870080226. [DOI] [PubMed] [Google Scholar]
  • 7.Gamboa ET, Wolf A, Yahr MD, Harter DH, Duffy PE, Barden H, Hsu KC. Influenza virus antigen in postencephalitic parkinsonism brain. Arch. Neurology. 1974;31:228–232. doi: 10.1001/archneur.1974.00490400042003. [DOI] [PubMed] [Google Scholar]
  • 8.Bojinov S. Encephalitis with acute parkinsonian syndrome and bilateral inflammatory necrosis of the substantia nigra. J. Neurol. Sci. 1971;12:383–415. doi: 10.1016/0022-510x(71)90109-2. [DOI] [PubMed] [Google Scholar]
  • 9.Shen WC, Ho YJ, Lee SK. MRI of transient postencephalitic parkinsonism. J. Comp. Assist. Tomogr. 1994;18:155–159. doi: 10.1097/00004728-199401000-00035. [DOI] [PubMed] [Google Scholar]
  • 10.Lin SK, Lu CS, Vingerhoets F, Snow BJ, Wai YY, Chu NS, Calne DB. Isolated involvement of substantia nigra in acute transient parkinsonism: MRI and, PET observations. 1995;1:67–72. doi: 10.1016/1353-8020(95)00017-8. [DOI] [PubMed] [Google Scholar]
  • 11.Geddes JF, Hughes AJ, Lees AJ, Daniel SE. Pathological overlap in cases of parkinsonism associated with neurofibrillary tangle. Brain. 1993;116:281–302. doi: 10.1093/brain/116.1.281. [DOI] [PubMed] [Google Scholar]
  • 12.Mattock C, Marmot M, Stern G. Could, Parkinson's disease follow intra-uterine influenza?: A speculative hypothesis. J. Neurol. Neurosurg. Psychiatry. 1988;51:753–756. doi: 10.1136/jnnp.51.6.753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Treves TA, Wechsler M, Rabey JM, Korczyn AD. Risk factors for Parkinson's disease: case-control study with temporal approach. Neurology. 1991;41(suppl 1):371. [Google Scholar]
  • 14.Marttila RJ, Halonen P, Rinne UK. Influenza virus antibodies in parkinsonism. Arch. Neurology. 1977;34:99–100. doi: 10.1001/archneur.1977.00500140053010. [DOI] [PubMed] [Google Scholar]
  • 15.Elizan TS, Madden DL, Noble GR, Herrmann KL, Gardner J, Schwartz J, Smith H, Sever JL, Yahr MD. Viral antibodies in serum and CSF of parkinsonian patients and controls. Arch. Neurology. 1979;36:529–534. doi: 10.1001/archneur.1979.00500450023002. [DOI] [PubMed] [Google Scholar]
  • 16.Schwartz J, Elizan TS. Search for viral particles and virus-specific products in idiopathic Parkinson disease brain material. Ann. Neurology. 1979;6:261–263. doi: 10.1002/ana.410060314. [DOI] [PubMed] [Google Scholar]
  • 17.Wetmur JG, Schwartz J, Elizan TS. Nucleic acid homology studies of viral nucleic acids in idiopathic Parkinson's disease. Arch. Neurology. 1979;36:462–464. doi: 10.1001/archneur.1979.00500440032004. [DOI] [PubMed] [Google Scholar]
  • 18.Fazzini E, Fleming J, Fahn S. Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson's disease. Mov. Disord. 1992;7:153–158. doi: 10.1002/mds.870070210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Rose E, Prabhaker P, Influenza A. Virus associated neurological disorders in Jamaica. West Indian Med. J. 1982;31:29–33. [PubMed] [Google Scholar]
  • 20.Frankova V, Jirasek A, Tumova B, Type A. Influenza: postmortem virus isolations from different organs in human lethal cases. Arch. Virology. 1977;53:265–268. doi: 10.1007/BF01314671. [DOI] [PubMed] [Google Scholar]
  • 21.Bradshaw GL, Schlesinger RW, Schwartz CD. Effects of cell differentiation on replication of A /WS/33, WSN, and, A./PR/8/34 influenza viruses in mouse brain cell cultures: biological and immunological characterization of products. J. Virology. 1989;63:1704–1714. doi: 10.1128/jvi.63.4.1704-1714.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Sugiura A, Ueda M. Neurovirulence of influenza virus in mice. Virology. 1980;101:440–449. doi: 10.1016/0042-6822(80)90457-2. [DOI] [PubMed] [Google Scholar]
  • 23.Nakajima S, Sugiura A. Neurovirulence of influenza virus in mice II. Mechanism of virulence as studied in a neuroblastoma cell line. Virology. 1980;101:450–457. doi: 10.1016/0042-6822(80)90458-4. [DOI] [PubMed] [Google Scholar]
  • 24.Reinacher M, Bonin J, Narayan O, Scholtissek C. Pathogenesis of neurovirulent influenza A virus infection in mice. Lab. Invest. 1983;49:686–692. [PubMed] [Google Scholar]
  • 25.Nagai Y. Protease-dependent virus tropism and pathogenicity. Trends in Microbiology. 1993;1:81–87. doi: 10.1016/0966-842X(93)90112-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Kido H, Yokogoshi Y, Sakai K, Tashiro M, Kishino M, Fukutomi A, Katunuma N. Isolation and characterization of a novel trypsin-like protease found in rat bronchiolar epithelial Clara cells. J. Biol. Chem. 1992;267:13573–13579. [PubMed] [Google Scholar]
  • 27.Yamada T, Nagai Y. Immunohistochemical studies of human tissues with antibody to factor, Xa. Histochem. J. 1996;28:73–77. doi: 10.1007/BF02331429. [DOI] [PubMed] [Google Scholar]
  • 28.Hinshaw VS, Olsen CW, Dybdahl-Sissoko N, Evans D. Apoptosis: a mechanism of cell killing by influenza A and, B viruses. J. Virology. 1994;68:3667–3673. doi: 10.1128/jvi.68.6.3667-3673.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Frielle DW, Huang DD, Youngner JS. Persistent infection with influenza A virus: evolution of virus mutants. Virology. 1984;138:103–117. doi: 10.1016/0042-6822(84)90151-x. [DOI] [PubMed] [Google Scholar]
  • 30.Lucas WT, Whitaker-Dowling P, Kaifer CR, Youngner JS. Characterization of a unique protein produced by influenza A virus recovered from a long-term persistent infection. Virology. 1988;166:620–623. doi: 10.1016/0042-6822(88)90538-7. [DOI] [PubMed] [Google Scholar]
  • 31.Tentsov YY, Zuev VA, Rzhaninova AA, Schevchenko AM, Bukrinskaya AG. Influenza virus genetic sequences in the blood of children with congenital pathology of the CNS. Arch. Virology. 1989;108:301–306. doi: 10.1007/BF01310943. [DOI] [PubMed] [Google Scholar]
  • 32.De BK, Nayak DP. Defective interfering influenza viruses and host cells: establishment and maintenance of persistent influenza virus infection in MDBK and HeLa cells. J. Virology. 1980;36:847–859. doi: 10.1128/jvi.36.3.847-859.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Takahashi M, Yamada T, Nakajima S, Nakajima K, Yamamoto T, Okada H. The substantia nigra is a major target for neurovirulent influenza A virus. J. Exp. Med. 1995;181:2161–2169. doi: 10.1084/jem.181.6.2161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Miyoshi K, Wolf A, Harter DH, Duffy PE, Gamboa ET, Hsu KC. Murine influenza virus encephalomyelitis. I. Neuropathological and immunofluorescence findings. J. Neuropath. Exp. Neurol. 1973;32:51–71. doi: 10.1097/00005072-197301000-00004. [DOI] [PubMed] [Google Scholar]
  • 35.Duffy PE, Wolf A, Hartner DH, Gamboa ET, Hsu KC. Murine influenza virus encephalomyelitis II. Electron-microscopic observation. J. Neuropathol. Exp. Neurol. 1973;32:72–91. doi: 10.1097/00005072-197301000-00005. [DOI] [PubMed] [Google Scholar]
  • 36.Yamada T, McGeer PL, McGeer EG. Lewy bodies in Parkinson's disease are recognized by antibodies to complement proteins. Acta Neuropathologica. 1992;84:100–104. doi: 10.1007/BF00427222. [DOI] [PubMed] [Google Scholar]
  • 37.Yamada T, Akiyama H, McGeer PL. Two types of spheroid bodies in the nigral neurons in Parkinson's disease. Can. J. Neurol. Sci. 1991;18:287–294. doi: 10.1017/s0317167100031838. [DOI] [PubMed] [Google Scholar]
  • 38.Yamada T, Akiyama H, McGeer PL. Complement-activated oligodendroglia: a new pathogenic entity identified by immunostaining with antibodies to human complement component proteins, C3d and, C4d. Neurosci. Lett. 1990;112:161–166. doi: 10.1016/0304-3940(90)90196-g. [DOI] [PubMed] [Google Scholar]
  • 39.Yamada T, Horisberger MA, Kawaguchi N, Moroo I. Immunohistochemistry using antibodies for α-interferon and its induced protein, MxA in Alzheimer and Parkinson's disease brain tissues. Neurosci. Lett. 1994;181:61–64. doi: 10.1016/0304-3940(94)90560-6. [DOI] [PubMed] [Google Scholar]
  • 40.Yamada T, Yamanaka I. Microglial localization of α-interferon receptor in human brain tissues. Neurosci. Lett. 1995;189:73–76. doi: 10.1016/0304-3940(95)11452-3. [DOI] [PubMed] [Google Scholar]
  • 41.Sen GC, Lengyel P. The interferon system. J. Biol. Chem. 1992;267:5017–5020. [PubMed] [Google Scholar]
  • 42.Tovey MG, Streul M, Gresser I, Gugenheim J, Blanchard B, Guymartho J, Vignaux F, Gigou M. Vol. 84. 1987. Interferon messenger RNA is produced constitutively in the organs of normal individuals; pp. 5038–5042. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Ho-Yen DO, Carrington D. Alpha-interferon responses in cerebrospinal fluid of patients with suspected meningitis. J. Clin. Pathol. 1987;40:83–86. doi: 10.1136/jcp.40.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Brandt ER, Mackay IR, Hertzog PJ, Cheetham BF, Sherritt M, Bernard CC. Molecular detection of interferon-α expression in multiple sclerosis brain. J. Neuroimmunology. 1993;44:1–6. doi: 10.1016/0165-5728(93)90261-v. [DOI] [PubMed] [Google Scholar]
  • 45.Akiyama H, Ikeda K, Katoh M, McGeer EG, McGeer PL. Expression of M. RP14, 27E10, interferon-α and leukocyte common antigen by reactive microglia in postmortem human brain tissue. J. Neuroimmunology. 1994;50:195–201. doi: 10.1016/0165-5728(94)90046-9. [DOI] [PubMed] [Google Scholar]
  • 46.Gupta SL, Raziuddin A, Sarkar FH. Receptors for human alpha interferon: Are ganglioside involved? J. Interferon Res. 1984;4:305–314. doi: 10.1089/jir.1984.4.305. [DOI] [PubMed] [Google Scholar]
  • 47.Rubinstein M, Orchansky P. The interferon receptors. CRC Crit. Rev. Biochem. 1986;21:249–275. doi: 10.3109/10409238609113613. [DOI] [PubMed] [Google Scholar]
  • 48.Novick D, Cohen B, Rubinstein M. Soluble interferon-α receptor molecules are present in body fluids. FEBS Lett. 1992;314:445–448. doi: 10.1016/0014-5793(92)81523-o. [DOI] [PubMed] [Google Scholar]
  • 49.Gardiner K, Horisberger MA, Kraus J, Tantravahi U, Rao V, Reddy S, Patterson D. Analysis of human chromosome 21: correlation of physical and cytogenetic maps; gene and CpG island distributions. EMBO J. 1990;9:25–34. doi: 10.1002/j.1460-2075.1990.tb08076.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Horisberger MA, McMaster GK, Zeller H, Wathelet MG, Dellis J, Content J. Cloning and sequence analysis of cDNAs for interferon- and virus-induced human Mx proteins reveal that they contain putative guanine nucleotide-binding sites: functional study of the corresponding gene promoter. J. Virology. 1990;64:1171–1181. doi: 10.1128/jvi.64.3.1171-1181.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Staehli P, Pavlovic J. Inhibition of vesicular stomatitis virus mRNA synthesis by human MxA protein. J. Virology. 1991;65:4498–4501. doi: 10.1128/jvi.65.8.4498-4501.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Pavlovic J, Haller O, Staeheli P. Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle. J. Virology. 1992;66:2564–2569. doi: 10.1128/jvi.66.4.2564-2569.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Schnorr J-J, Schneider-Schaulies S, Simon-Jödicke A, Pavlovic J, Horisberger MA, Meulen V. MxA-dependent inhibition of measles virus glycoprotein synthesis in a stably transfected human monocytic cell line. J. Virology. 1993;67:4760–4768. doi: 10.1128/jvi.67.8.4760-4768.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Horisberger MA. Interferon-induced human protein MxA is a GTPase which binds transiently to cellular proteins. J. Virology. 1992;66:4705–4709. doi: 10.1128/jvi.66.8.4705-4709.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Nakayama M, Yazaki K, Kusano A, Nagata K, Hanai N, Ishihama A. Structure of mouse Mx1 protein. J. Biol. Chem. 1993;268:15033–15038. [PubMed] [Google Scholar]
  • 56.Pitossi F, Blank A, Schröder A, Hüssi P, Schwemmle M, Pavlovic J, Staeheli P. A functional, GTP-binding motif is necessary for antiviral activity of Mx proteins. J. Virology. 1993;67:6726–6732. doi: 10.1128/jvi.67.11.6726-6732.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Yamada T. Further observations on MxA-positive Lewy bodies in, Parkinson's disease brain tissues. Neurosci. Lett. 1995;195:41–44. doi: 10.1016/0304-3940(95)11777-t. [DOI] [PubMed] [Google Scholar]
  • 58.Pollanen MS, Dickson DW, Bergeron C. Pathology and biology of the Lewy body. J. Neuropathol Exp. Neurol. 1993;52:183–191. doi: 10.1097/00005072-199305000-00001. [DOI] [PubMed] [Google Scholar]
  • 59.Kristensen K. Potential role of viruses in neurodegeneration. Mol. Chem. Neuropathol. 1992;16:45–58. doi: 10.1007/BF03159960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Wheeler JG, Winkler LS, Seeds M, Bass D, Abramson JS. Influenza A virus alters structural and biochemical functions of the neutrophil cytoskeleton. J. Leukocyte Biol. 1990;47:332–343. doi: 10.1002/jlb.47.4.332. [DOI] [PubMed] [Google Scholar]
  • 61.Caldwell SE, Cassidy LF, Abramson JS. Alterations in cell protein phosphorylation in human neutrophils exposed to influenza A virus. J. Immunology. 1988;140:3560–3567. [PubMed] [Google Scholar]

Articles from Parkinsonism & Related Disorders are provided here courtesy of Elsevier

RESOURCES