Advanced

Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain

Thakur, Poonam LU ; Breger, Ludivine S. LU ; Lundblad, Martin LU ; Wan, Oi Wan LU ; Mattsson, Bengt LU ; Luk, Kelvin C.; Lee, Virginia Man Yee; Trojanowski, John Q and Björklund, Anders LU (2017) In Proceedings of the National Academy of Sciences of the United States of America 114(39). p.8284-8293
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AAV, Adenoassociated virus, Microglia, Phospho-synuclein, Synuclein protofibrils
in
Proceedings of the National Academy of Sciences of the United States of America
volume
114
issue
39
pages
8284 - 8293
publisher
National Acad Sciences
external identifiers
  • scopus:85029948737
  • wos:000411704000020
ISSN
0027-8424
DOI
10.1073/pnas.1710442114
language
English
LU publication?
yes
id
643f63a4-b390-42ac-b294-1c3ebe2391fa
date added to LUP
2017-10-05 13:20:52
date last changed
2018-01-16 13:21:02
@article{643f63a4-b390-42ac-b294-1c3ebe2391fa,
  abstract     = {<p>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<sup>+</sup> and CD8<sup>+</sup> 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.</p>},
  author       = {Thakur, Poonam and Breger, Ludivine S. and Lundblad, Martin and Wan, Oi Wan and Mattsson, Bengt and Luk, Kelvin C. and Lee, Virginia Man Yee and Trojanowski, John Q and Björklund, Anders},
  issn         = {0027-8424},
  keyword      = {AAV,Adenoassociated virus,Microglia,Phospho-synuclein,Synuclein protofibrils},
  language     = {eng},
  month        = {09},
  number       = {39},
  pages        = {8284--8293},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain},
  url          = {http://dx.doi.org/10.1073/pnas.1710442114},
  volume       = {114},
  year         = {2017},
}