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.


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


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