Tags

Type your tag names separated by a space and hit enter

Modeling Parkinson's disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain.
Proc Natl Acad Sci U S A. 2017 09 26; 114(39):E8284-E8293.PN

Abstract

Although a causative role of α-synuclein (α-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration. We show that the ability of human α-syn fibrils to trigger Lewy-like α-synuclein pathology in the affected DA neurons is dramatically enhanced in the presence of elevated levels of human α-syn. This synucleinopathy was fully developed already 10 days after fibril injection, accompanied by progressive degeneration of dopaminergic neurons in SN, neuritic swelling, reduced striatal DA release, and impaired motor behavior. Moreover, a prominent inflammatory response involving both activation of resident microglia and infiltration of CD4+ and CD8+ T lymphocytes was observed. Hypertrophic microglia were found to enclose or engulf cells and processes containing Lewy-like α-syn aggregates. α-Syn aggregates were also observed inside these cells, suggesting transfer of phosphorylated α-syn from the affected nigral neurons. The nigral pathology triggered by fibrils in combination with AAV-mediated overexpression of α-syn reproduced many of the cardinal features of the human disease. The short time span and the distinct sequence of pathological and degenerative changes make this combined approach attractive as an experimental model for the assessment of neuroprotective and disease-modifying strategies.

Authors+Show Affiliations

Wallenberg Neuroscience Center, Neurobiology Division, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.Wallenberg Neuroscience Center, Neurobiology Division, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.Wallenberg Neuroscience Center, Neurobiology Division, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.Wallenberg Neuroscience Center, Neurobiology Division, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.Wallenberg Neuroscience Center, Neurobiology Division, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104. Institute on Aging, University of Pennsylvania, Philadelphia, PA 19104.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104. Institute on Aging, University of Pennsylvania, Philadelphia, PA 19104.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104. Institute on Aging, University of Pennsylvania, Philadelphia, PA 19104.Wallenberg Neuroscience Center, Neurobiology Division, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; anders.bjorklund@med.lu.se.

Pub Type(s)

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

Language

eng

PubMed ID

28900002

Citation

Thakur, Poonam, et al. "Modeling Parkinson's Disease Pathology By Combination of Fibril Seeds and Α-synuclein Overexpression in the Rat Brain." Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 39, 2017, pp. E8284-E8293.
Thakur P, Breger LS, Lundblad M, et al. Modeling Parkinson's disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain. Proc Natl Acad Sci U S A. 2017;114(39):E8284-E8293.
Thakur, P., Breger, L. S., Lundblad, M., Wan, O. W., Mattsson, B., Luk, K. C., Lee, V. M. Y., Trojanowski, J. Q., & Björklund, A. (2017). Modeling Parkinson's disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain. Proceedings of the National Academy of Sciences of the United States of America, 114(39), E8284-E8293. https://doi.org/10.1073/pnas.1710442114
Thakur P, et al. Modeling Parkinson's Disease Pathology By Combination of Fibril Seeds and Α-synuclein Overexpression in the Rat Brain. Proc Natl Acad Sci U S A. 2017 09 26;114(39):E8284-E8293. PubMed PMID: 28900002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modeling Parkinson's disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain. AU - Thakur,Poonam, AU - Breger,Ludivine S, AU - Lundblad,Martin, AU - Wan,Oi Wan, AU - Mattsson,Bengt, AU - Luk,Kelvin C, AU - Lee,Virginia M Y, AU - Trojanowski,John Q, AU - Björklund,Anders, Y1 - 2017/09/12/ PY - 2017/9/14/pubmed PY - 2018/6/6/medline PY - 2017/9/14/entrez KW - AAV KW - adenoassociated virus KW - microglia KW - phospho-synuclein KW - synuclein protofibrils SP - E8284 EP - E8293 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 114 IS - 39 N2 - Although a causative role of α-synuclein (α-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration. We show that the ability of human α-syn fibrils to trigger Lewy-like α-synuclein pathology in the affected DA neurons is dramatically enhanced in the presence of elevated levels of human α-syn. This synucleinopathy was fully developed already 10 days after fibril injection, accompanied by progressive degeneration of dopaminergic neurons in SN, neuritic swelling, reduced striatal DA release, and impaired motor behavior. Moreover, a prominent inflammatory response involving both activation of resident microglia and infiltration of CD4+ and CD8+ T lymphocytes was observed. Hypertrophic microglia were found to enclose or engulf cells and processes containing Lewy-like α-syn aggregates. α-Syn aggregates were also observed inside these cells, suggesting transfer of phosphorylated α-syn from the affected nigral neurons. The nigral pathology triggered by fibrils in combination with AAV-mediated overexpression of α-syn reproduced many of the cardinal features of the human disease. The short time span and the distinct sequence of pathological and degenerative changes make this combined approach attractive as an experimental model for the assessment of neuroprotective and disease-modifying strategies. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/28900002/Modeling_Parkinson's_disease_pathology_by_combination_of_fibril_seeds_and_α_synuclein_overexpression_in_the_rat_brain_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=28900002 DB - PRIME DP - Unbound Medicine ER -