中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (10): 2019-2020.doi: 10.4103/1673-5374.308080

• 观点:退行性病与再生 • 上一篇    下一篇

Necrostatin-1在帕金森病模型中的双重作用

  

  • 出版日期:2021-10-15 发布日期:2021-03-19

The dual role of necrostatin-1 in Parkinson’s disease models

Eva Alegre-Cortés,  Guadalupe Martínez-Chacón,  José M. Fuentes*,  Sokhna M. S. Yakhine-Diop*   

  1. Universidad de Extremadura, Depto. Bioquímica y Biología Molecular y Genética, Facultad de Enfermería y Terapia Ocupacional, Avda de la Universidad s/n, Cáceres, Spain (Alegre-Cortés E, Martínez-Chacón G, Fuentes JM, Yakhine-Diop SMS) 
    Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) Madrid, Spain (Martínez-Chacón G, Fuentes JM, Yakhine-Diop SMS) 
    Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Cáceres, Spain (Martínez-Chacón G, Fuentes JM, Yakhine-Diop SMS) 
  • Online:2021-10-15 Published:2021-03-19
  • Contact: José M. Fuentes, PhD, jfuentes@unex.es; Sokhna M. S. Yakhine-Diop, PhD, smsyakhinediop@unex.es.
  • Supported by:
    We thank FUNDESALUD for helpful assistance.

    This work was supported by grants from Junta de Extremadura, Spain, No. IB18048 (to EAC), the ONCE Foundation (to GMC), the Isabel Gemio Foundation (to SMSYD), the Instituto de Salud Carlos III, CIBERNED, No. CB06/05/004 (to JMF), and partially supported by the “Fondo Europeo de Desarrollo Regional” (FEDER) from the European Union.  

摘要:

Neural Regen ResNecrostatin-1对帕金森病模型的毒性及神经保护作用

 

Necrostatin-1Nec-1)抑制受体相互作用蛋白(RIP1RIP3和混合谱系激酶域样(MLKL)蛋白的后续激活和相互作用调节,从而产生坏死性调亡。MLKL蛋白对于质膜的破裂和细胞内物质的释放触发炎症、氧化应激和细胞死亡至关重要。Nec-1已被证实在帕金森病(PD)等神经退行性疾病的不同细胞和动物模型中具有神经保护作用。尽管Nec-1也与非坏死性细胞死亡的抑制有关,但它确实是RIP1激酶活性的抑制剂。Nec-1类似物,例如Nec-1s(稳定的变体),在抑制丝氨酸/苏氨酸蛋白激酶的活性方面似乎更有效。坏死性调亡的激活通常与肿瘤坏死因子(TNF)受体途径有关,但活性氧(ROS)和神经毒素的大量生成可导致RIP1RIP3蛋白的级联激活。

 

来自西班牙埃斯特雷马杜拉大学的Eva Alegre-Cortés所在团队最近的研究表明PD患者细胞中存在未激活程序性坏死,但暴露于鱼藤酮的细胞中确激活了程序性坏死。Nec-1作为一种坏死性调亡的抑制剂,可以预防鱼藤酮诱导的PD模型中的坏死性调亡。但是,Nec-1影响线粒体的形态,不能保护线粒体免受鱼藤酮的毒性。因此,Alegre-Cortés团队认为通过抑制PTEN诱导的假定激酶/ Parkin介导的线粒体吞噬作用,Nec-1影响线粒体形态和线粒体清除,从而增强帕金森毒素的作用。他们认为把Nec-1与其他调节自噬/有丝分裂和氧化应激的药物结合起来将会非常有趣。

 

文章在《中国神经再生研究(英文版)》杂志20211010期发表。

https://orcid.org/0000-0001-6910-2089 (José M. Fuentes);
https://orcid.org/0000-0002-4868-3352 (Sokhna M. S. Yakhine-Diop)

Abstract: Neuronal cell death is the main hallmark of Parkinson’s disease (PD). It is an irreversible process promoted by neurotoxins and/or genetic mutations. Different types of cell death have been associated with PD. The mechanisms by which neurons decide to specific type of cell death remain elusive. However, it is well known that cell death can be either programmed or not. Apoptosis is a programmed cell death that involves the release of cytochrome c from damaged mitochondria to cytosol and the activation of caspases leading to nuclear condensation. Necrosis is a caspase-independent cell death characterized by a gain in cell volume, rupture of plasma membrane and leak of cell contents, inflammation, and affects neighbouring cells. It was classified as a non-programmed cell death, but there are types of necrotic death triggered by a protein activation cascade, including necroptosis.