Cell, 2022-05, Vol.185 (11), p.1943-1959.e21
2022
Details
- Autor(en) / Beteiligte
- Titel
- PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson’s disease
- Ist Teil von
- Cell, 2022-05, Vol.185 (11), p.1943-1959.e21
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2022
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •Pathologic α-synuclein neurodegeneration occurs via PAAN/MIF nuclease activity•Genetic depletion and nuclease-deficient MIF prevents α-synuclein neurodegeneration•Identification of a first-in class MIF nuclease inhibitor, PAANIB-1•PAANIB-1 prevents neurodegeneration in multiple models of Parkinson’s disease Neurodegeneration in Parkinson’s disease occurs via PAAN/MIF nuclease activity and is amenable to inhibition with a brain-penetrant small molecule inhibitor.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2022.04.020Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9149120
- Format
- –
- Schlagworte
- Animals, Brain - metabolism, cell death, Disease Models, Animal, Dopaminergic Neurons - metabolism, Endonucleases - metabolism, Intramolecular Oxidoreductases - metabolism, Macrophage Migration-Inhibitory Factors - metabolism, Mice, MIF, neurodegeneration, Parkinson Disease - drug therapy, Parkinson Disease - genetics, Parkinson Disease - metabolism, Parkinson’s disease, PARP1, parthanatos, synuclein