PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease

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

doi:10.1016/j.cell.2022.04.020

PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease

Cell. 2022 May 26;185(11):1943-1959.e21. doi: 10.1016/j.cell.2022.04.020. Epub 2022 May 10.

Authors

Hyejin Park¹, Tae-In Kam¹, Hanjing Peng², Shih-Ching Chou³, Amir A Mehrabani-Tabari⁴, Jae-Jin Song⁵, Xiling Yin⁵, Senthilkumar S Karuppagounder⁵, George K Umanah⁵, A V Subba Rao², YuRee Choi⁵, Akanksha Aggarwal⁴, Sohyun Chang⁴, Hyunhee Kim⁵, Jiyoung Byun⁴, Jun O Liu², Ted M Dawson⁶, Valina L Dawson⁷

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ 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.
⁶ 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. Electronic address: tdawson@jhmi.edu.
⁷ 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. Electronic address: vdawson@jhmi.edu.

Abstract

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.

Keywords: MIF; PARP1; Parkinson’s disease; cell death; neurodegeneration; parthanatos; synuclein.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism
Disease Models, Animal
Dopaminergic Neurons / metabolism
Endonucleases / metabolism
Intramolecular Oxidoreductases / metabolism*
Macrophage Migration-Inhibitory Factors / metabolism*
Mice
Parkinson Disease* / drug therapy
Parkinson Disease* / genetics
Parkinson Disease* / metabolism

Substances

Macrophage Migration-Inhibitory Factors
Endonucleases
Intramolecular Oxidoreductases
Mif protein, mouse

Grants and funding

R37 NS067525/NS/NINDS NIH HHS/United States