Parthanatos Pathway Linked to Neuron Loss in Multiple Sclerosis | Medical Xpress

Multiple sclerosis (MS) is a chronic, often debilitating autoimmune disease affecting the central nervous system (CNS). The disease disrupts communication between the brain and body by attacking the myelin sheath, the protective covering of nerve fibers, leading to inflammation and lesions. While treatments exist to manage relapses, preventing lasting neuronal damage has remained a significant challenge. Now, research published in Nature Neuroscience suggests a specific cellular process, called parthanatos, plays a key role in this neuronal loss, potentially opening new avenues for therapeutic intervention.

Symptoms of MS are highly variable, depending on which areas of the CNS are affected. These can range from vision problems and muscle weakness to numbness, fatigue, balance issues, and cognitive difficulties. Understanding the precise mechanisms driving neuronal death in MS is crucial for developing more effective treatments.

Unraveling the Role of Parthanatos in Neuroinflammation

Researchers at Johns Hopkins University School of Medicine investigated the contribution of parthanatos – a distinct form of programmed cell death – to neuron loss in the context of neuroinflammation, such as that seen in MS. Their study, utilizing a mouse model of MS known as experimental autoimmune encephalomyelitis (EAE), and analysis of human patient tissue, revealed a link between immune responses and the activation of this internal cell death program. The study builds on earlier work identifying parthanatos as a cell death pathway triggered by severe damage to cellular genetic material, activating enzymes that fragment the cell’s genome.

“My laboratory has been studying therapeutic targets on immune cells for over 30 years,” explained senior author Peter A. Calabresi to Medical Xpress. “We now have quite a few FDA-approved therapies for MS and related neuroimmune diseases, but these do not slow the insidious progression that ensues years after the immune attacks on the brain and spinal cord. The purpose of this study was to identify how the neurons die following inflammation in the CNS to determine if we could intervene at this downstream stage of the neurodegenerative process.”

The research team examined brain and spinal cord tissue from EAE mice at different stages of the disease, employing molecular techniques to assess DNA integrity and identify markers of parthanatos, such as proteins involved in DNA fragmentation. They found that neurons experienced immune-mediated injury through oxidative stress and exhibited signs of DNA damage early in the disease process, suggesting parthanatos was involved. Specifically, the pathway involves the release of PAR into the cytoplasm, triggering the release of AIF, which binds to MIF and allows MIF to translocate to the nucleus where it acts as a nuclease, ultimately killing the neuron. This pathway was previously described in Parkinson’s Disease by collaborators at Johns Hopkins.

Blocking MIF Nuclease Activity Offers Neuroprotection

To further investigate the role of parthanatos, the researchers genetically and pharmacologically blocked the final stage of the process – the activity of MIF nuclease, the enzyme responsible for DNA damage. Remarkably, inhibiting this enzyme reduced DNA fragmentation, promoted neuron survival, and lessened the severity of symptoms in the EAE mice. EAE is a widely used animal model to study MS, mimicking many of the disease’s key features.

“We were able to show that blocking MIF’s nuclease activity selectively using transgenic mice or a small molecule inhibitor significantly protected both ventral horn motor neurons and retinal ganglion cells in the EAE mice,” said Calabresi.

Implications for Future MS Therapies

This study represents the first evidence linking parthanatos triggered by neuroinflammation to substantial neuron loss in a mouse model of MS. While further research is needed to confirm these findings in humans, the discovery of parthanatos and MIF nuclease as potential therapeutic targets offers a promising new direction for MS treatment development. Medical Xpress reports that the researchers are now planning to examine the long-term effects of blocking MIF nuclease activity and explore potential overlap with another cell death pathway, ferroptosis.

The identification of parthanatos as an immune-triggered cell death pathway in MS is a novel finding. The ability to inhibit MIF nuclease activity using both genetic and pharmacological approaches provides a potential strategy for treating progressive MS and related neurodegenerative diseases. This work could ultimately lead to the development of new drugs or genetic interventions aimed at preventing neuronal death in MS, potentially alleviating the severity of symptoms experienced by patients.

The research team acknowledges that further investigation is needed to fully understand the role of parthanatos in MS and to determine the safety and efficacy of targeting this pathway in humans. Still, these findings represent a significant step forward in our understanding of the complex mechanisms underlying neuronal damage in MS and offer hope for the development of more effective treatments.

This article was written by Ingrid Fadelli, edited by Gaby Clark, and fact-checked and reviewed by Robert Egan.