| First Author | Park H | Year | 2022 |
| Journal | Cell | Volume | 185 |
| Issue | 11 | Pages | 1943-1959.e21 |
| PubMed ID | 35545089 | Mgi Jnum | J:324824 |
| Mgi Id | MGI:7281645 | Doi | 10.1016/j.cell.2022.04.020 |
| Citation | Park H, et al. (2022) PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease. Cell 185(11):1943-1959.e21 |
| abstractText | 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 alpha-synuclein (alpha-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 alpha-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 alpha-syn PFF, AAV-alpha-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. |
