title: Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration.
abstract: Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA. Electronic address: kpaumier@yahoo.com.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Paumier
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Kelvin C
authors.initials: KC
authors.lastname: Luk
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
authors.forename: Fredric P
authors.initials: FP
authors.lastname: Manfredsson
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Kanaan
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Lipton
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Collier
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Steece-Collier
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Celano
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Schulz
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Ivette M
authors.initials: IM
authors.lastname: Sandoval
authors.affiliation: Department of Psychology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Fleming
authors.affiliation: Department of Psychology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Elliott
authors.initials: E
authors.lastname: Dirr
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Nicole K
authors.initials: NK
authors.lastname: Polinski
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
authors.forename: Caryl E
authors.initials: CE
authors.lastname: Sortwell
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014828:Vocalization, Animal / Q000187:drug effects; D051844:alpha-Synuclein / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D051844:alpha-Synuclein
keywords: Alpha-synuclein; Neurodegeneration; Parkinson's disease; Pre-formed fibrils; Propagation; Rats