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Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration.
Neurobiol Dis. 2015 Oct; 82:185-199.ND

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.

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Authors+Show Affiliations

Paumier KL
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.
Luk KC
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Manfredsson FP
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
Kanaan NM
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
Lipton JW
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
Collier TJ
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
Steece-Collier K
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.
Kemp CJ
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
Celano S
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
Schulz E
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
Sandoval IM
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
Fleming S
Department of Psychology, University of Cincinnati, Cincinnati, OH, USA.
Dirr E
Department of Psychology, University of Cincinnati, Cincinnati, OH, USA.
Polinski NK
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
Trojanowski JQ
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Lee VM
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Sortwell CE
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA.

MeSH

AnimalsCorpus StriatumDisease Models, AnimalDopaminergic NeuronsMaleMiceMotor ActivityNerve DegenerationRatsRats, Sprague-DawleySubstantia NigraVocalization, Animalalpha-Synuclein

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26093169

Citation

Paumier, Katrina L., et al. "Intrastriatal Injection of Pre-formed Mouse Α-synuclein Fibrils Into Rats Triggers Α-synuclein Pathology and Bilateral Nigrostriatal Degeneration." Neurobiology of Disease, vol. 82, 2015, pp. 185-199.
Paumier KL, Luk KC, Manfredsson FP, et al. Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis. 2015;82:185-199.
Paumier, K. L., Luk, K. C., Manfredsson, F. P., Kanaan, N. M., Lipton, J. W., Collier, T. J., Steece-Collier, K., Kemp, C. J., Celano, S., Schulz, E., Sandoval, I. M., Fleming, S., Dirr, E., Polinski, N. K., Trojanowski, J. Q., Lee, V. M., & Sortwell, C. E. (2015). Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiology of Disease, 82, 185-199. https://doi.org/10.1016/j.nbd.2015.06.003
Paumier KL, et al. Intrastriatal Injection of Pre-formed Mouse Α-synuclein Fibrils Into Rats Triggers Α-synuclein Pathology and Bilateral Nigrostriatal Degeneration. Neurobiol Dis. 2015;82:185-199. PubMed PMID: 26093169.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. AU - Paumier,Katrina L, AU - Luk,Kelvin C, AU - Manfredsson,Fredric P, AU - Kanaan,Nicholas M, AU - Lipton,Jack W, AU - Collier,Timothy J, AU - Steece-Collier,Kathy, AU - Kemp,Christopher J, AU - Celano,Stephanie, AU - Schulz,Emily, AU - Sandoval,Ivette M, AU - Fleming,Sheila, AU - Dirr,Elliott, AU - Polinski,Nicole K, AU - Trojanowski,John Q, AU - Lee,Virginia M, AU - Sortwell,Caryl E, Y1 - 2015/06/17/ PY - 2015/04/12/received PY - 2015/06/08/revised PY - 2015/06/09/accepted PY - 2015/6/21/entrez PY - 2015/6/21/pubmed PY - 2016/8/20/medline KW - Alpha-synuclein KW - Neurodegeneration KW - Parkinson's disease KW - Pre-formed fibrils KW - Propagation KW - Rats SP - 185 EP - 199 JF - Neurobiology of disease JO - Neurobiol Dis VL - 82 N2 - 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. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/26093169/Intrastriatal_injection_of_pre_formed_mouse_α_synuclein_fibrils_into_rats_triggers_α_synuclein_pathology_and_bilateral_nigrostriatal_degeneration_ DB - PRIME DP - Unbound Medicine ER -