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

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

Cell (2022-05-12)
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
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.

MATERIALS
Product Number
Brand
Product Description

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