美国约翰霍普金斯大学Valina L. Dawson研究团队发现，抑制PAAN/MIF核酸酶可防止帕金森病的神经退行性。相关论文于2022年5月10日在线发表于国际学术期刊《细胞》。
研究人员表示，parthanatos（一种新的细胞死亡形式）相关凋亡诱导因子（AIF）核酸酶（PAAN），也被称为巨噬细胞迁移抑制因子（MIF），是PD-D/E（X）K核酸酶的成员，在parthanatos中起最后的执行者作用。PAAN在帕金森病（PD）中的作用以及它是否可被化学抑制尚不清楚。
研究人员表明，病理性α-突触蛋白（α-syn）诱导的神经变性是通过PAAN/MIF核酸酶活性发生的。PAAN/MIF的遗传耗竭和缺乏核酸酶活性的突变体可防止散发性PD的α-syn预成纤维（PFF）小鼠模型中多巴胺能神经元的缺失和行为缺陷。通过化合物筛选，研究人员发现了PAANIB-1，这是一种脑渗透性的PAAN/MIF核酸酶抑制剂，可以防止α-syn PFF、AAV-α-syn过表达或MPTP中毒在体内诱发的神经退行性。这项发现可能在人类病症中具有广泛的意义，在这些病症中，parthanatos在开发针对可药用的PAAN/MIF核酸酶的细胞死亡抑制剂方面发挥着作用。
附：英文原文
Title: PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson’s disease
Author: Hyejin Park, Tae-In Kam, Hanjing Peng, Shih-Ching Chou, Amir A. Mehrabani-Tabari, Jae-Jin Song, Xiling Yin, Senthilkumar S. Karuppagounder, George K. Umanah, A.V. Subba Rao, YuRee Choi, Akanksha Aggarwal, Sohyun Chang, Hyunhee Kim, Jiyoung Byun, Jun O. Liu, Ted M. Dawson, Valina L. Dawson
Issue&Volume: 2022-05-10
Abstract: Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also knownas macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleasesthat acts as a final executioner in parthanatos. PAAN’s role in Parkinson’s disease(PD) and whether it is amenable to chemical inhibition is not known. Here, we showthat neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIFnuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activityprevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformedfibril (PFF) mouse model of sporadic PD. Compound screening led to the identificationof PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegenerationinduced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos playsa role in the development of cell death inhibitors targeting the druggable PAAN/MIFnuclease.
DOI: 10.1016/j.cell.2022.04.020
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00467-6