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首页> 外文期刊>Neurobiology of disease >Intrastriatal injection of pre-formed mouse alpha-synuclein fibrils into rats triggers alpha-synuclein pathology and bilateral nigrostriatal degeneration
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Intrastriatal injection of pre-formed mouse alpha-synuclein fibrils into rats triggers alpha-synuclein pathology and bilateral nigrostriatal degeneration

机译：将大鼠预先形成的小鼠α-突触核蛋白原纤维纹状体内注射触发α-突触核蛋白病理学和双侧黑质纹状体变性

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Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (alpha-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated alpha-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse alpha-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant alpha-syn or PFF mouse alpha-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant alpha-syn and PFF alpha-syn injections resulted in phosphotylated alpha-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). alpha-Syn accumulations co-localized with ubiguitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although alpha-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-daytime-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that alpha-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous alpha-syn to induce a progressive, neurodegenerative model of alpha-synucleinopathy in rats. (C) 2015 Elsevier Inc. All rights reserved.
机译：以前的研究表明，向小鼠纹状体内注射原纤维α-突触核蛋白（α-syn）会诱发帕金森氏病（PD）样的路易体（LB）病理，这种病理是由在解剖学上相互连接的区域中聚集的α-syn和明显的黑纹状体变性所形成的。本研究的目的是评估注射到大鼠纹状体中的外源性小鼠α-syn预形成的原纤维（PFF）是否会导致LB样细胞内包裹物的积累和黑质纹状体变性。 Sprague-Dawley大鼠在1或2位接受单侧纹状体内非原纤维化重组α-syn或PFF小鼠α-syn注射，并在注射后30、60或180天安乐死。非原纤维化重组α-syn和PFFα-syn注射均导致磷酸化的α-syn神经内神经蓄积（即弥漫性路易神经突（LN）-和LB-样内含物），在PFF注射后具有明显更大的积累。在支配纹状体的几个区域中观察到了类似LB的包裹体，最突出的是额叶和岛状皮层，杏仁核和黑质致密部（SNpc）。 α-Syn积累与泛素，p62共定位，并且对硫黄素-S阳性和蛋白酶-k耐药，表明PFF诱导的病理表现出与人LB类似的特性。尽管SNpc中的α-syn夹杂物仍与纹状体注射同侧，但我们在1-位和2-位PFF注射范例中在180天时间点观察到了双侧黑质多巴胺神经元的减少。 PFF注射的大鼠在60天和180天时纹状体多巴胺能神经支配双侧减少，而高香草酸双侧减少。然而，仅在注射PFF的同侧纹状体中观察到多巴胺减少。尽管在180天注射PFF的大鼠中多巴胺的不对称程度不足以引起苯丙胺诱导的旋转运动不足或前肢在缸工作中使用，但仍观察到超声发声的明显破坏。两者合计，我们的发现表明，α-synPFF足以播种内源性α-syn的病理转化和繁殖，从而诱发大鼠α-突触核蛋白病的进行性神经退行性模型。 （C）2015 Elsevier Inc.保留所有权利。

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