PNAS:这个分子能够阻断和恢复帕金森氏症引起的神经变性
2018/10/02
帕金森病(PD)的特征是多巴胺能神经元的逐渐丧失,这是目前的治疗方法无法预防的。近日,巴塞罗那自治大学研究人员发现,SynuClean-D分子可以阻断导致帕金森病发作的聚集物形成,并恢复了帕金森病引起的神经变性。


UAB的Jordi Pujols,Salvador Ventura和SamuelPeña,图片来源:UAB

研究结果以“Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons”为题发表在《PNAS》杂志上。


https://doi.org/10.1073/pnas.1804198115

帕金森病是继阿尔茨海默病之后第二常见的不可治愈的神经退行性疾病。其特征在于以淀粉样蛋白纤维形式在多巴胺能神经元中积累蛋白质沉积。这些聚集物主要是由α-突触核蛋白以非常复杂的方式形成的,这使得识别能够预防或恢复该过程的分子以及与其相关的神经变性变得复杂。

由巴塞罗那自治大学生物技术与生物医学研究所(IBB)的研究人员领导的这项科学合作发现了一种能够阻止和逆转这种神经变性的分子。在分析了超过14000个分子后,他们发现了SynuClean-D分子,可以抑制α-突触核蛋白的聚集,并破坏已经形成的淀粉样纤维,从而阻止了神经退行性帕金森病的发生。

通过对神经退行性疾病中最常用的动物模型之一秀丽隐杆线虫进行实验,研究人员证实,通过食物给药,该分子能够显着减少α-突触核蛋白聚集,防止有毒聚集体的扩散,从而避免了多巴胺能神经元的变性。

为了鉴定SynuClean-D,研究人员开发了一种方法,能够在数千种分子中识别α-突触核蛋白聚集抑制剂。一旦鉴定出来,研究人员就对它们的抑制活性进行体外生物物理特征分析和试验,通过人类神经细胞培养来观察它们的行为,并在动物模型(秀丽隐杆线虫)上测试它们的行为。这些动物在肌肉或多巴胺能神经元中表达α-突触核蛋白。实验表明,使用该抑制剂可以减少蛋白质的聚集,改善了动物的活动性并保护其免于神经变性。

“一切似乎都表明,我们确定的分子SynuClean-D,可能在未来为帕金森等神经退行性疾病提供治疗应用,” UAB研究员兼研究协调员Salvador Ventura指出。

责编:风

参考资料

Molecule capable of halting and reverting neurodegeneration caused by Parkinson's disease identified

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neuronsMolecule capable of halting and reverting neurodegeneration caused by Parkinson's disease identified

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  • Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

    Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.

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