MIF Nuclease actions in Synuclein Dementias

Project Summary/Abstract: The pathologic accumulation of misfolded α-synuclein (α-syn) in neurons leads to neurodegeneration and cognitive dysfunction and dementia in a family of disorders designated α-synucleinopathies, which includes Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) dementia (PDD). DLB and PDD are clinically similar and share characteristic neuropathologic changes. Recent studies indicate that activation of poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) contributes to the neurodegeneration induced by pathologic α-syn through the Parthanatos associated AIF (apoptosis-inducing factor) Nuclease (PAAN) also known as MIF, where PAAN/MIF is the executioner of parthanatic cell death via its nuclease activity. This form of cell death has been designated parthanatos to distinguish it from other types of cell death such as apoptosis, necroptosis or autophagic death. Interference with each step of the parthanatic cascade has been shown to be neuroprotective in a variety of disease models. Recently, MIF nuclease activity was shown to be required for neurodegeneration of dopamine neurons in three orthogonal models of PD. Importantly, the role of PAAN/MIF nuclease activity in the cognitive dysfunction in α-synucleinopathies is not known. Moreover, the effect of PAAN/MIF nuclease-specific inhibitors in α-synucleinopathies cognitive dysfunction has not been investigated. MIF has also been suggested to be required for inflammasome activation. MIF possesses both nuclease and tautomerase activity that act independently of one another. It is not known whether PAAN/MIF’s nuclease activity plays a role in activation of the double strand DNA sensor cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) and subsequent STING (stimulator of interferon genes) pathway and inflammasome activation. What role MIF’s tautomerase activity plays in inflammasome activation is also not known. Determining whether MIF nuclease activity or tautomerase activity is required for cGas-STING pathway activation is important since it could direct the development and use of specific MIF inhibitors to prevent cGas-STING pathway and inflammasome activation. Accordingly, in this project we will examine the neurobehavior and neuropathology of pathologic α-syn in the gut-brain model in MIF wild type and MIF E22Q (nuclease-deficient) and MIF P2G KI (tautomerase-deficient) mice and test whether the brain penetrant MIF nuclease inhibitor, PAANIB-1, can prevent the spread of pathologic α-syn and cognitive behavioral abnormalities in the gut-brain model in behaviorally presymptomatic and symptomatic mice. In addition, we will determine whether MIF nuclease activity is required for cGas-STING pathway and inflammasome activation in pathologic α-syn induced neurodegeneration and explore the role of neuronal versus microglial MIF nuclease activity in pathologic α- syn induced cognitive dysfunction and neurodegeneration.