title: Hypothesis: a role for EBV-induced molecular mimicry in Parkinson's disease.
abstract: Current concepts regarding the pathogenesis of Parkinson's disease support a model whereby environmental factors conspire with a permissive genetic background to initiate the disease. The identity of the responsible environmental trigger has remained elusive. There is incontrovertible evidence that aggregation of the neuronal protein alpha-synuclein is central to disease pathogenesis. A novel hypothesis of Parkinson's pathogenesis, articulated by Braak and colleagues, implicates a pathogen acting in the olfactory mucosa and gastrointestinal tract as the inciting agent. In this point-of-view article, we hypothesize that α-synuclein aggregation in Parkinson's disease is an Epstein-Barr virus (EBV)-induced autoimmune phenomenon. Specifically, we have shown evidence for molecular mimicry between the C-terminal region of α-synuclein and a repeat region in the latent membrane protein 1 encoded by EBV. We hypothesize that, in genetically-susceptible individuals, anti-EBV latent membrane protein antibodies targeting the critical repeat region cross react with the homologous epitope on α-synuclein and induce its oligomerization. Consistent with the Braak's proposed pattern of spread, we contend that axon terminals in the lamina propria of the gut are among the initial targets, with subsequent spread of pathology to the CNS. While at this time, we can only provide evidence from the literature and preliminary findings from our own laboratory, we hope that our hypothesis will stimulate the development of tractable experimental systems that can be exploited to test it. Further support for an EBV-induced immune pathogenesis for Parkinson's disease could have profound therapeutic implications.
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada. Electronic address: jwoulfe@ottawahospital.on.ca.
authors.forename: John M
authors.initials: JM
authors.lastname: Woulfe
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Madison T
authors.initials: MT
authors.lastname: Gray
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Gray
authors.affiliation: Department of Pathology, St. Michael's Hospital, Toronto, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Munoz
authors.affiliation: Department of Pathology, VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Jaap M
authors.initials: JM
authors.lastname: Middeldorp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D018716:Molecular Mimicry / Q000502:physiology*; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics* / Q000821:virology*
keywords: Alpha-synuclein; Autoimmunity; Epstein–Barr virus; Molecular mimicry; Parkinson's disease