Morphological and behavioral impact of AAV2/5-mediated overexpression of human wildtype alpha-synuclein in the rat nigrostriatal system.
Morphological and behavioral impact of AAV2/5-mediated overexpression of human wildtype alpha-synuclein in the rat nigrostriatal system.
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DOI：
10.1371/journal.pone.0081426
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sortwell CE
中科院分区：
文献类型：
--
作者：
Gombash SE;Manfredsson FP;Kemp CJ;Kuhn NC;Fleming SM;Egan AE;Grant LM;Ciucci MR;MacKeigan JP;Sortwell CE
α-突触核蛋白（α-syn）参与帕金森病（PD）发病机制的发现导致了病毒载体介导的α-syn过表达啮齿动物模型的开发和使用。这些系列实验的目的是表征在大鼠黑质（SN）中注射表达人野生型α-syn的重组腺相关病毒（rAAV）血清型2/5导致的神经变性和功能缺陷。将表达rAAV 2/5的绿色荧光蛋白（GFP，1.2 x 1013）或不同滴度（2.2 x 1012、1.0 x 1013、5.9 x 1013或1.0 x 1014）的rAAV 2/5-α-syn单侧注射到SN的两个部位。在载体注射后4、8或12周对大鼠组实施安乐死。酪氨酸羟化酶免疫反应（THir）神经元死亡的严重程度，在SN的延髓部（SNPC）是依赖于载体滴度。在1.0 × 1014滴度rAAV 2/5-α-syn注射后4周和1.0 × 1013滴度rAAV 2/5-α-syn注射后8周观察到相同程度的黑质纹状体变性（60-70% SNpc THir神经元变性和40-50%纹状体TH表达丧失）。THir神经元变性在SNpc的整个头-尾轴上是相对均匀的。尽管1.0 x 1013和1.0 x 1014 rAAV 2/5-α-syn组之间的黑质纹状体变性相当，但仅在α-syn表达持续时间较长的8周大鼠中观察到圆柱体试验和调整步骤任务的功能障碍。运动障碍的缸任务是高度相关的纹状体TH损失。此外，在5.9 X 1013 rAAV 2/5-α-syn注射后8周，观察到超声发声缺陷。总之，我们的rAAV 2/5-α-syn过表达模型证明了稳健的黑质纹状体α-syn过表达，诱导显著的黑质纹状体变性，其是载体和持续时间依赖性的，并且在特定参数下可导致与纹状体TH去神经支配水平直接相关的运动损伤。
The discovery of the involvement of alpha-synuclein (α-syn) in Parkinson’s disease (PD) pathogenesis has resulted in the development and use of viral vector-mediated α-syn overexpression rodent models. The goal of these series of experiments was to characterize the neurodegeneration and functional deficits resulting from injection of recombinant adeno-associated virus (rAAV) serotype 2/5-expressing human wildtype α-syn in the rat substantia nigra (SN). Rats were unilaterally injected into two sites in the SN with either rAAV2/5-expressing green fluorescent protein (GFP, 1.2 x 1013) or varying titers (2.2 x 1012, 1.0 x 1013, 5.9 x 1013, or 1.0 x 1014) of rAAV2/5-α-syn. Cohorts of rats were euthanized 4, 8, or 12 weeks following vector injection. The severity of tyrosine hydroxylase immunoreactive (THir) neuron death in the SN pars compacta (SNpc) was dependent on vector titer. An identical magnitude of nigrostriatal degeneration (60-70% SNpc THir neuron degeneration and 40-50% loss of striatal TH expression) was observed four weeks following 1.0 x 1014 titer rAAV2/5-α-syn injection and 8 weeks following 1.0 x 1013 titer rAAV2/5-α-syn injection. THir neuron degeneration was relatively uniform throughout the rostral-caudal axis of the SNpc. Despite equivalent nigrostriatal degeneration between the 1.0 x 1013 and 1.0 x 1014 rAAV2/5-α-syn groups, functional impairment in the cylinder test and the adjusting steps task was only observed in rats with the longer 8 week duration of α-syn expression. Motor impairment in the cylinder task was highly correlated to striatal TH loss. Further, 8 weeks following 5.9 x 1013 rAAV2/5-α-syn injection deficits in ultrasonic vocalizations were observed. In conclusion, our rAAV2/5-α-syn overexpression model demonstrates robust nigrostriatal α-syn overexpression, induces significant nigrostriatal degeneration that is both vector and duration dependent and under specific parameters can result in motor impairment that directly relates to the level of striatal TH denervation.
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影响因子：
5.3
作者：
Decressac, M.;Mattsson, B.;Bjorklund, A.
通讯作者：
Bjorklund, A.
DOI：
10.1016/j.bbrc.2011.07.028
发表时间：
2011-09-09
影响因子：
3.1
作者：
Lee, Hak Joo;Kang, Shin Jung;Im, Hana
通讯作者：
Im, Hana
DOI：
10.1016/j.bbadis.2009.07.007
发表时间：
2010-01
影响因子：
6.2
作者：
Devi, Latha;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.
影响因子：
4.8
作者：
Nakamura, Ken;Nemani, Venu M.;Edwards, Robert H.
通讯作者：
Edwards, Robert H.
影响因子：
2.6
作者：
Brudzynski, SM
通讯作者：
Brudzynski, SM