title: Brain injection of α-synuclein induces multiple proteinopathies, gliosis, and a neuronal injury marker.
abstract: Intracerebral injection of amyloidogenic α-synuclein (αS) has been shown to induce αS pathology in the CNS of nontransgenic mice and αS transgenic mice, albeit with varying efficiencies. In this study, using wild-type human αS transgenic mice (line M20), we demonstrate that intracerebral injection of recombinant amyloidogenic or soluble αS induces extensive αS intracellular inclusion pathology that is associated with robust gliosis. Near the injection site, a significant portion of αS inclusions are detected in neurons but also in astrocytes and microglia. Aberrant induction of expression of the intermediate filament protein peripherin, which is associated with CNS neuronal injury, was also observed predominantly near the site of injection. In addition, many pSer129 αS-induced inclusions colocalize with the low-molecular-mass neurofilament subunit (NFL) or peripherin staining. αS inclusion pathology was also induced in brain regions distal from the injection site, predominantly in neurons. Unexpectedly, we also find prominent p62-immunoreactive, αS-, NFL-, and peripherin-negative inclusions. These findings provide evidence that exogenous αS challenge induces αS pathology but also results in the following: (1) a broader disruption of proteostasis; (2) glial activation; and (3) a marker of a neuronal injury response. Such data suggest that induction of αS pathology after exogenous seeding may involve multiple interdependent mechanisms.
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: Alex B
authors.initials: AB
authors.lastname: McKinney
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thomas
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, College of Medicine University of Florida, Gainesville, Florida 32610, and EnCor Biotechnology, Gainesville, Florida 32608.
authors.forename: Gerry
authors.initials: G
authors.lastname: Shaw
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, College of Medicine University of Florida, Gainesville, Florida 32610, and 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, and McKnight Brain Institute, College of Medicine University of Florida, Gainesville, Florida 32610, and bgiasson@ufl.edu tgolde@ufl.edu.
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
mesh_terms: D000818:Animals; D005911:Gliosis / Q000139:chemically induced* / Q000473:pathology*; D051379:Mice; D008845:Microinjections / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D057177:TDP-43 Proteinopathies / Q000139:chemically induced* / Q000473:pathology*; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D051844:alpha-Synuclein
keywords: Parkinson's disease; alpha-synuclein; amyloid; neurofilament; pathology; peripherin