# Inhibition of MIF nuclease-mediated parthanatos prevents neuron and oligodendrocyte death in the context of multiple sclerosis

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary
Nearly three million people worldwide are currently living with multiple sclerosis (MS), a complex neurological disease
that primarily affects individuals between 20-45 years of age. MS is characterized by peripheral immune cell infiltration
into the central nervous system (CNS) with associated reactive gliosis, oligodendrocyte (OL) death, demyelination, and
neuroaxonal degeneration. Some of the infiltrates that migrate to the CNS are lymphocytes that target the myelin sheaths of
axons. Existing therapies predominately inhibit adaptive immune cells in circulation; however, these medications are often
not effective in halting the pathophysiology that underlies progressive CNS degeneration in MS, where immune cell
infiltration and activation are minimal. No therapies currently exist to treat this pathology because the molecular
mechanisms by which CNS lesions occur in patients with MS is not fully understood. Since disability in progressive MS is
driven by the chronic loss of OLs and neurons, this study will investigate the distinct degenerative process of both cell types
utilizing relevant models. The ultimate objective of this proposed research is to identify how neurons and OLs die in the
context of MS. Understanding this will help identify therapeutic targets to stop these degenerative processes from occurring
in patients with MS. For the past decade, our lab has studied a novel, non-apoptotic cell death pathway, parthanatos, that
plays an active role in various neurological conditions. Parthanatos-inducing conditions that lead to DNA damage, such as
high ROS concentrations, are pathologically prevalent across many neurological diseases including MS. Herein, our lab has
created a mouse line with a point mutation that selectively ablates the enzymatic activity of the downstream executioner of
parthanatos cell death, macrophage migration inhibitory factor (MIF) nuclease, and synthesized a compound that
specifically inhibits MIF nuclease. Both genetic and pharmacologic developments have been shown to mediate protection
of dopaminergic neurons in the alpha-synuclein plaque-forming fibril model of Parkinson’s Disease. These experimental
tools will be used here to assess the therapeutic efficacy of targeting MIF nuclease in the experimental autoimmune
encephalomyelitis (EAE) mouse model of MS and neonatal-derived mouse OLs following exposure to MS-relevant insults.
My preliminary data suggest that genetic ablation of MIF nuclease in EAE mice led to decreased neurologic impairment
over time. Importantly, genetic ablation of MIF nuclease in EAE mice did not affect peak EAE disease severity or peripheral
immune cell infiltration into the spinal cord. I also determined that genetic ablation and pharmacologic inhibition of MIF
nuclease in EAE mice protected against retinal ganglion cell and lumbar spinal cord neuron loss. I further revealed that OL
precursor cells underwent parthanatos following DNA damage, and that this cell death process...

## Key facts

- **NIH application ID:** 10815210
- **Project number:** 1F31NS132520-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jackson Mace
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2023-12-04 → 2027-06-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815210

## Citation

> US National Institutes of Health, RePORTER application 10815210, Inhibition of MIF nuclease-mediated parthanatos prevents neuron and oligodendrocyte death in the context of multiple sclerosis (1F31NS132520-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10815210. Licensed CC0.

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