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Poly (ADP-ribose) (PAR)-dependent cell death in neurodegenerative diseases.
International Review of Cell and Molecular Biology ( IF 6.420 ) Pub Date : 2020-01-27 , DOI: 10.1016/bs.ircmb.2019.12.009
Hyejin Park 1 , Tae-In Kam 1 , Ted M Dawson 2 , Valina L Dawson 3
Affiliation  

Disruption of cellular functions with aging-induced accumulation of neuronal stressors causes cell death which is a common feature of neurodegenerative diseases. Studies in a variety of neurodegenerative disease models demonstrate that poly (ADP-ribose) (PAR)-dependent cell death, also named parthanatos, is responsible for neuronal loss in neurological diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Parthanatos has distinct features that differ from caspase-dependent apoptosis, necrosis or autophagic cell death. Parthanatos can be triggered by the accumulation of PAR due to overactivation of PAR polymerase-1 (PARP-1). Excess PAR, induces the mitochondrial release apoptosis-inducing factor (AIF), which binds to macrophage migration inhibitory factor (MIF) carrying MIF into the nucleus where it cleaves genomic DNA into large fragments. In this review, we will discuss the molecular mechanisms of parthanatos and their role in neurodegenerative diseases. Furthermore, we will discuss promising therapeutic interventions within the pathological PAR signaling cascade that could be designed to halt the progression of neurodegeneration.

中文翻译:

在神经退行性疾病中,聚(ADP-核糖)(PAR)依赖性细胞死亡。

衰老引起的神经元应激源累积破坏细胞功能会导致细胞死亡,这是神经退行性疾病的常见特征。对多种神经退行性疾病模型的研究表明,聚(ADP-核糖)(PAR)依赖性细胞死亡(也称为parthanatos)是造成神经系统疾病(如帕金森氏病(PD),阿尔茨海默氏病(AD))的神经元丢失的原因,亨廷顿舞蹈病(HD)和肌萎缩性侧索硬化症(ALS)。Parthanatos具有与caspase依赖性凋亡,坏死或自噬细胞死亡不同的特征。由于PAR聚合酶1(PARP-1)的过度活化,PAR的积累可能触发Parthanatos。过量的PAR诱导线粒体释放凋亡诱导因子(AIF),它与巨噬细胞迁移抑制因子(MIF)结合,将MIF带入细胞核,并在其中将基因组DNA切割成大片段。在这篇综述中,我们将讨论parthanatos的分子机制及其在神经退行性疾病中的作用。此外,我们将讨论病理性PAR信号传导级联中有希望的治疗干预措施,该干预措施可被设计为阻止神经变性的进展。
更新日期:2020-01-27
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