title: Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity.
abstract: The accumulation and propagation of misfolded α-synuclein (α-Syn) is a central feature of Parkinson's disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) α-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-α-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing α-Syn pathology in primary neurons or after intracerebral injection into wild-type mice. Chimeric α-Syn fibrils demonstrate enhanced or reduced pathogenicities compared with wild-type Hu- or Ms-α-Syn fibrils. Furthermore, α-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting that transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous α-Syn seeds and endogenous neuronal α-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility.
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA. Electronic address: kelvincl@upenn.edu.
authors.forename: Kelvin C
authors.initials: KC
authors.lastname: Luk
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Covell
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Kehm
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
authors.forename: Insung Y
authors.initials: IY
authors.lastname: Song
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Byrne
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
authors.forename: Rose M
authors.initials: RM
authors.lastname: Pitkin
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
authors.forename: Samantha C
authors.initials: SC
authors.lastname: Decker
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-4283 USA. Electronic address: vmylee@upenn.edu.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D013045:Species Specificity; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000682:Amyloid; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein