PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson’s disease,Cell

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PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson’s disease
Cell ( IF 45.5 ) Pub Date : 2022-05-10 , DOI: 10.1016/j.cell.2022.04.020
Hyejin Park ₁ , Tae-In Kam ₁ , Hanjing Peng ₂ , Shih-Ching Chou ₃ , Amir A Mehrabani-Tabari ₄ , Jae-Jin Song ₅ , Xiling Yin ₅ , Senthilkumar S Karuppagounder ₅ , George K Umanah ₅ , A V Subba Rao ₂ , YuRee Choi ₅ , Akanksha Aggarwal ₄ , Sohyun Chang ₄ , Hyunhee Kim ₅ , Jiyoung Byun ₄ , Jun O Liu ₂ , Ted M Dawson ₆ , Valina L Dawson ₇

Affiliation

Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Department of Pharmacology and Molecular Sciences and SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that 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 show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.

中文翻译：

PAAN/MIF 核酸酶抑制可预防帕金森病的神经变性

Parthanatos 相关凋亡诱导因子 (AIF) 核酸酶 (PAAN)，也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 中充当最终执行者。PAAN 在帕金森病 (PD) 中的作用以及它是否适合化学抑制尚不清楚。在这里，我们表明病理性 α-突触核蛋白 (α-syn) 诱导的神经变性是通过 PAAN/MIF 核酸酶活性发生的。PAAN/MIF 的遗传缺失和缺乏核酸酶活性的突变体可防止散发性 PD 的 α-syn 预制原纤维 (PFF) 小鼠模型中多巴胺能神经元的丢失和行为缺陷。化合物筛选导致 PAANIB-1 的鉴定，PAANIB-1 是一种脑渗透性 PAAN/MIF 核酸酶抑制剂，可防止由 α-syn PFF、AAV-α-syn 过表达或 MPTP 中毒引起的神经变性体内。我们的发现可能与人类病理学有广泛的相关性，其中 parthanatos 在针对可药物 PAAN/MIF 核酸酶的细胞死亡抑制剂的开发中发挥作用。

更新日期：2022-05-10

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