title: Prion infection promotes extensive accumulation of α-synuclein in aged human α-synuclein transgenic mice.
abstract: In neurodegenerative disorders of the aging population, misfolded proteins, such as PrP(Sc), α-synuclein, amyloid β protein and tau, can interact resulting in enhanced aggregation, cross seeding and accelerated disease progression. Previous reports have shown that in Creutzfeldt-Jakob disease and scrapie, α-synuclein accumulates near PrP(Sc) deposits. However, it is unclear if pre-existing human α-synuclein aggregates modified prion disease pathogenesis, or if PrP(Sc) exacerbates the α-synuclein pathology. Here, we inoculated infectious prions into aged α-synuclein transgenic (tg) and non-transgenic littermate control mice by the intracerebral route. Remarkably, inoculation of RML and mNS prions into α-synuclein tg mice resulted in more extensive and abundant intraneuronal and synaptic α-synuclein accumulation. In addition, infectious prions led to the formation of perineuronal α-synuclein deposits with a neuritic plaque-like appearance. Prion pathology was unmodified by the presence of α-synuclein. However, with the mNS prion strain there was a modest but significant acceleration in the time to terminal prion disease in mice having α-synuclein aggregates as compared with non-tg mice. Taken together, these studies support the notion that PrP(Sc) directly or indirectly promotes α-synuclein pathology.
authors.affiliation: Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA. emasliah@ucsd.edu
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Chandra
authors.initials: C
authors.lastname: Inglis
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bett
authors.forename: Melanie
authors.initials: M
authors.lastname: Lucero
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
mesh_terms: D000375:Aging; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism*; D012608:Scrapie / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D018620:PrPSc Proteins; D051844:alpha-Synuclein