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《Acta Laboratorium Animalis Scientia Sinica》 2018-05
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Establishment of a transgenic rat model of Parkinson’s disease with an α-synuclein A30P mutation

SONG Na;WANG Haijun;LI Hongbin;SHAO Minglong;ZHANG Wei;GU Tengteng;HU Qing;YU Jian;ZHANG Jinghang;SU Wei;ZHAO Tiesuo;LI Yushan;School of Basic Medical Sciences;School of Public Health;Henan Mental Hospital,Henan Key Lab of Biological Psychiatry,the Second Affiliated Hospital;the First Affiliated Hospital,Xinxiang Medical University;  
Objective The aim of this study was to develop a transgenic rat model of Parkinson's disease by lentiviral vector-mediated overexpression of human α-synuclein in the substantia nigra of rats. Methods Lentiviral expression vectors were constructed by inserting the normal α-synuclein gene(WT) or the α-synuclein gene with an A30 P mutation(A30 P) downstream of the Cytomegalovirus(CMV) promoter(pLKO-CMV-α-SYN-WT-P2 A-GFP and pLKO2-CMV-α-SYN-A30 P-P2 A-GFP). The vectors were transduced into 293 FT cells, and α-synuclein protein levels were detected by western blotting after transient transfection for 24 h. Following the packaging, enrichment, the viral suspension with control, and normal or mutated forms of α-synuclein, were stereotaxically injected into the substantia nigra. After 21 days, the rats were euthanized, and the substantia nigra harvested and processed for immunofluorescence to detect α-synuclein and tyrosine hydroxylase(TH) expression, and changes in numbers of neurons. Motor performance was also assessed in the A30 P rats using the rotating rod test. Results Each lentiviral vector induced equivalent levels of normal or A30 P mutated α-synuclein expression. Compared with the control group, both the wild type and A30 P mutant groups showed an obvious reduction in numbers of dopaminergic neurons in the substantia nigra, with significantly greater injury in the A30 P group. Immunofluorescence staining experiments in the injured region of A30 P mutant rats showed largely absent TH staining, but abundant α-synuclein immunoreactive aggregation. The human α-synuclein group was also associated with a marked reduction in TH expression, indicating that A30 P mutant overexpression caused neuronal degeneration. In addition, A30 P mutant rats showed a progressive decline in motor performance. Conclusions We have established a human α-synuclein A30 P transgenic rat model of Parkinson's disease, which may be useful for understanding the pathogenesis and developing treatments for this disorder.
【Fund】: 国家自然科学基金项目(81602132);; 河南省科技攻关项目(172102310584 182102310242);; 新乡医学院博士科研启动基金(XYBSKYZZ201512 201513 201802)~~
【CateGory Index】: R742.5;R-332
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