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

Pharmacologic inhibition of MIF nuclease: A new treatment paradigm to treat cell death

“…The fact that MIF's nuclease activity drives neuronal loss and is separable from its other functions prompted the exploration of specific inhibitors to MIF's nuclease activity while leaving MIF's other functions intact. Excitingly, our group discovered PAANIB‐1, a first‐in‐class brain‐penetrant inhibitor of MIF nuclease activity that does not interfere with MIF's tautomerase or cytokine activities 13 . PAANIB‐1 provided robust neuroprotection and prevented neurobehavioural deficits in three mouse models of PD, highlighting its promise as a potential disease‐modifying therapy for disorders in which parthanatos plays a role.…”

“… 10,12 Interfering with MIF's nuclease activity, but not MIF's tautomerase activity, reduces neuronal injury and behavioural deficits after middle cerebral artery occlusion in mice 10 . Moreover, MIF nuclease‐deficient (E22Q MIF) mice, but not MIF tautomerase‐deficient (P2G MIF) mice, are spared from PD pathology and the accompanying behavioural and motor deficits in a mouse model of sporadic PD 13 . The fact that MIF's nuclease activity drives neuronal loss and is separable from its other functions prompted the exploration of specific inhibitors to MIF's nuclease activity while leaving MIF's other functions intact.…”

“…10 Moreover, MIF nuclease-deficient (E22Q MIF) mice, but not MIF tautomerase-deficient (P2G MIF) mice, are spared from PD pathology and the accompanying behavioural and motor deficits in a mouse model of sporadic PD. 13 The fact that MIF's nuclease activity drives neuronal loss and is separable from its other functions prompted the exploration of specific inhibitors to MIF's nuclease activity while leaving MIF's other functions intact. Excitingly, our group discovered PAANIB-1, a first-in-class brainpenetrant inhibitor of MIF nuclease activity that does not interfere with MIF's tautomerase or cytokine activities.…”

“…Excitingly, our group discovered PAANIB-1, a first-in-class brainpenetrant inhibitor of MIF nuclease activity that does not interfere with MIF's tautomerase or cytokine activities. 13 PAANIB-1 provided robust neuroprotection and prevented neurobehavioural deficits in three mouse models of PD, highlighting its promise as a potential disease-modifying therapy for disorders in which parthanatos plays a role.…”

“…Since MIF nuclease is not structurally similar to other human nucleases, MIF nuclease inhibitors would not interfere with the function of other human nucleases. 13 Thus, to date, all indications suggest that it has minimal liabilities, while on the other hand, tremendous potential as a new treatment paradigm for cell death for a variety of disorders. Potent, selective and specific MIF nuclease brain-penetrant inhibitors with appropriate safety and metabolic profiles hold particular promise for treating many neurodegenerative disorders 14 and diseases beyond the nervous system.…”