Targeting PAAN/MIF nuclease activity in parthanatos-associated brain diseases

Current FDA-approved drugs for neurodegenerative diseases primarily aim to reduce pathological protein aggregation or alleviate symptoms by enhancing neurotransmitter signaling. However, outcomes remain suboptimal and often fail to modify the course of neurodegenerative diseases. Acute neurologic injury that occurs in stroke and traumatic brain injury (TBI) also suffer from inadequate therapies to prevent neuronal cell death, resulting from both the acute insult and the subsequent reperfusion injury following recanalization of the occlusion in stroke. Approaches to prevent neuronal loss in neurodegenerative disease and acute neurologic injury hold significant therapeutic promise. Parthanatos is a cell death pathway that is activated and plays an integral role in these neurologic disorders. Parthanatos-associated apoptosis-inducing factor nuclease (PAAN), also known as macrophage migration inhibitory factor (MIF) nuclease, is the final executioner in the parthanatic cell death cascade. We posit that inhibiting parthanatos by blocking MIF nuclease activity offers a promising and precise strategy to prevent neuronal cell death in both chronic neurodegenerative disease and acute neurologic injury. In this chapter, we discuss the role of MIF's nuclease activity - distinct from its other enzymatic activities - in driving cell death that occurs in various neurological diseases. We also delve into the discovery, screening, structure, and function of MIF nuclease inhibitors, which have demonstrated neuroprotection in Parkinson's disease (PD) cell and mouse models. This analysis includes essential future research directions and queries that need to be considered to advance the clinical development of MIF nuclease inhibitors. Ultimately, our discussion aims to inspire drug development centered around inhibiting MIF's nuclease activity, potentially resulting in transformative, disease-modifying therapeutics.