Modeling Parkinson's Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers.
Modeling Parkinson's Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers.
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DOI：
10.3390/ijms21228535
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发表时间：
2020-11-12
影响因子：
5.6
通讯作者：
Carta AR
中科院分区：
文献类型：
--
作者：
Boi L;Pisanu A;Palmas MF;Fusco G;Carboni E;Casu MA;Satta V;Scherma M;Janda E;Mocci I;Mulas G;Ena A;Spiga S;Fadda P;De Simone A;Carta AR
聚集的α-突触核蛋白（αSyn）的积累是帕金森病（PD）的标志。目前的证据表明，小的可溶性αSyn寡聚体（αSynOs）是αSyn聚集体中毒性最大的种类，并且大小和拓扑结构特性是α SynOs介导的毒性的关键因素，涉及与神经元或胶质细胞的相互作用。我们先前表征了具有促进对神经元膜的毒性的特定结构特性的人αSynO（H-αSynO）。在这里，我们测试了这些H-α SynO在体内的神经毒性潜力，与PD的神经病理学和症状特征相关。将H-αSynOs注入大鼠黑质丘脑腹侧部（SNpc）。在进行性时间点测量磷酸化αSyn（p129-αSyn）、反应性小胶质细胞和细胞因子水平。此外，在小胶质细胞预暴露于α synO后进行体外吞噬测定。评估多巴胺能损失、运动和认知表现。H-αSynOs触发SNpc神经元和小胶质细胞中的p129-αSyn沉积并扩散到纹状体。在SNPC中诱导早期和持续的神经炎症反应。在体外，H-αSynOs抑制小胶质细胞的吞噬功能。注射H-α synOs的大鼠表现出SNpc神经元的早期线粒体丢失和异常，随后是黑质纹状体多巴胺能的逐渐丢失，与运动和认知障碍相关。脑内接种具有结构特征的H-αSynOs提供了大鼠进行性PD神经病理学模型，这将有助于测试神经保护疗法。
The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies.
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影响因子：
16.6
作者：
Fusco, Giuliana;Pape, Tillmann;Stephens, Amberley D.;Mahou, Pierre;Costa, Ana Rita;Kaminski, Clemens F.;Schierle, Gabriele S. Kaminski;Vendruscolo, Michele;Veglia, Gianluigi;Dobson, Christopher M.;De Simone, Alfonso
通讯作者：
De Simone, Alfonso
影响因子：
8.6
作者：
Espa, Elena;Clemensson, Erik K. H.;Cenci, M. Angela
通讯作者：
Cenci, M. Angela
DOI：
10.1073/pnas.1421204112
发表时间：
2015-04-21
影响因子：
11.1
作者：
Chen, Serene W.;Drakulic, Srdja;Cremades, Nunilo
通讯作者：
Cremades, Nunilo
影响因子：
4.8
作者：
Froula, Jessica M.;Castellana-Cruz, Marta;Volpicelli-Daley, Laura A.
通讯作者：
Volpicelli-Daley, Laura A.
影响因子：
12.7
作者：
Faustini, Gaia;Longhena, Francesca;Bellucci, Arianna
通讯作者：
Bellucci, Arianna