PARP and MIF Nuclease Actions in Tauopathies
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PROJECT SUMMARY/ABSTRACT: The pathologic accumulation of misfolded and tau in neurons leads to neurodegeneration and cognitive dysfunction and dementia in tauopathies. Accumulating evidence suggests that activation of poly(ADP- ribose) (PAR) polymerase 1 (PARP1) contributes to neuronal cell death in acute and chronic neurologic disorders through the Parthanatos associated AIF (apoptosis-inducing factor) Nuclease (PAAN) also known as MIF, where 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 in orthogonal models of α-synuncleinopathy induced neurodegeneration. The role of PARP1 and MIF nuclease activity in the cognitive dysfunction in pathologic tau induced neurodegeneration is not known. 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 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 in response to pathologic tau. What role MIF’s tautomerase activity plays in inflammasome activation is also not known. Accordingly, in this project we will examine the neurobehavior and neuropathology of PS19 mice in PARP1 knock out mice and in MIF E22Q (nuclease-deficient) and MIF P2G KI (tautomerase-deficient) mice and test whether these genetic interventions can prevent pathologic tau cognitive abnormalities and neurodegeneration. In addition, we will determine whether MIF nuclease activity is required for cGAS-STING pathway, the interferon response and inflammasome activation in pathologic tau induced neurodegeneration and explore the role of neuronal versus microglial MIF nuclease activity in pathologic tau induced cognitive dysfunction and neurodegeneration.
