title: Distinct α-synuclein strains differentially promote tau inclusions in neurons.
abstract: Many neurodegenerative diseases are characterized by the accumulation of insoluble protein aggregates, including neurofibrillary tangles comprised of tau in Alzheimer's disease and Lewy bodies composed of α-synuclein in Parkinson's disease. Moreover, different pathological proteins frequently codeposit in disease brains. To test whether aggregated α-synuclein can directly cross-seed tau fibrillization, we administered preformed α-synuclein fibrils assembled from recombinant protein to primary neurons and transgenic mice. Remarkably, we discovered two distinct strains of synthetic α-synuclein fibrils that demonstrated striking differences in the efficiency of cross-seeding tau aggregation, both in neuron cultures and in vivo. Proteinase K digestion revealed conformational differences between the two synthetic α-synuclein strains and also between sarkosyl-insoluble α-synuclein extracted from two subgroups of Parkinson's disease brains. We speculate that distinct strains of pathological α-synuclein likely exist in neurodegenerative disease brains and may underlie the tremendous heterogeneity of synucleinopathies.
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jing L
authors.initials: JL
authors.lastname: Guo
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Covell
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Daniels
authors.forename: Michiyo
authors.initials: M
authors.lastname: Iba
authors.forename: Anna
authors.initials: A
authors.lastname: Stieber
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Riddle
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000682:Amyloid; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D016875:tau Proteins