# MIF Nuclease actions in Synuclein Dementias

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $818,421

## Abstract

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.

## Key facts

- **NIH application ID:** 10815118
- **Project number:** 1R01AG085688-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** VALINA L. DAWSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $818,421
- **Award type:** 1
- **Project period:** 2023-12-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815118

## Citation

> US National Institutes of Health, RePORTER application 10815118, MIF Nuclease actions in Synuclein Dementias (1R01AG085688-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10815118. Licensed CC0.

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