title: Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice.
abstract: It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in αS homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.
authors.affiliation: Department of Neuroscience,Center for Translational Research in Neurodegenerative Disease, and.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Sacino
authors.affiliation: Department of Neuroscience,Center for Translational Research in Neurodegenerative Disease, and.
authors.forename: Mieu
authors.initials: M
authors.lastname: Brooks
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thomas
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, and.
authors.forename: Alex B
authors.initials: AB
authors.lastname: McKinney
authors.affiliation: Department of Neuroscience,McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610.
authors.forename: Sooyeon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, and.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Regenhardt
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, and.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: McGarvey
authors.affiliation: Department of Neuroscience,Center for Translational Research in Neurodegenerative Disease, and.
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Ayers
authors.affiliation: Department of Neuroscience,McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610.
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
authors.affiliation: Department of Neuroscience,Center for Translational Research in Neurodegenerative Disease, andMcKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610.
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.affiliation: Department of Neuroscience,Center for Translational Research in Neurodegenerative Disease, andMcKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610 bgiasson@ufl.edu tgolde@ufl.edu.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: Department of Neuroscience,Center for Translational Research in Neurodegenerative Disease, andMcKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610 bgiasson@ufl.edu tgolde@ufl.edu.
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007273:Injections, Intramuscular; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D010641:Phenotype; D016019:Survival Analysis; D051844:alpha-Synuclein / Q000008:administration & dosage* / Q000378:metabolism*
chemical_list: C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein
keywords: Parkinson disease; amyloid