Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain.
Proc Natl Acad Sci USA. 2017-09-12; 114(39): E8284-E8293
DOI: 10.1073/pnas.1710442114
Lire sur PubMed
1. Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):E8284-E8293. doi:
10.1073/pnas.1710442114. Epub 2017 Sep 12.
Modeling Parkinson’s disease pathology by combination of fibril seeds and
α-synuclein overexpression in the rat brain.
Thakur P(1), Breger LS(1), Lundblad M(1), Wan OW(1), Mattsson B(1), Luk KC(2)(3),
Lee VMY(2)(3), Trojanowski JQ(2)(3), Björklund A(4).
Author information:
(1)Wallenberg Neuroscience Center, Neurobiology Division, Department of
Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
(2)Center for Neurodegenerative Disease Research, Department of Pathology and
Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
(3)Institute on Aging, University of Pennsylvania, Philadelphia, PA 19104.
(4)Wallenberg Neuroscience Center, Neurobiology Division, Department of
Experimental Medical Science, Lund University, 221 84 Lund, Sweden;
.
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.
DOI: 10.1073/pnas.1710442114
PMCID: PMC5625925
PMID: 28900002 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.