Multiple sclerosis (MS) is a chronic, often debilitating autoimmune disease that affects the central nervous system (CNS). This disease causes the immune system to mistakenly attack the protective sheath surrounding nerve fibers (i.e., myelin), which leads to inflammation and lesions, disrupting the electrical signals connecting the brain and the body.
The symptoms of MS can vary greatly depending on the regions attacked by the immune system. They can range from vision problems to muscle weakness, numbness, fatigue, issues with balance and mental difficulties.
While there are now treatments that can reduce the risk of MS relapses, entirely preventing damage to neurons caused by the disease has so far proved challenging. One reason for this is that the molecular mechanisms via which MS-related inflammation results in the death or degradation of brain cells have not yet been clearly elucidated.
Researchers at Johns Hopkins University School of Medicine recently carried out a mouse study investigating the possible contribution of a specific molecular process that leads to cell death, called parthanatos, in the loss of neurons resulting from neuroinflammation, such as that associated with MS. Their findings, published in Nature Neuroscience, suggest that damage to neurons associated with MS is caused by immune responses that trigger internal cell death programs.
“My laboratory has been studying therapeutic targets on immune cells for over 30 years,” Peter A. Calabresi, senior author of the paper, told 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.”
Studying brain cell death linked to autoimmune inflammation
Earlier studies uncovered a form of programmed cell death called parthanatos, occurring when severe damage to genetic material inside cells activates enzymes that in turn break a cell’s genome apart. Calabresi and his colleagues wanted to shed light on the molecular pathways that lead to cell death in MS, assessing the possible role of parthanatos.
To do this, they studied a mouse model of MS known as experimental autoimmune encephalomyelitis (EAE). In addition, they studied neurons and tissues extracted from human patients who were diagnosed with MS.
The researchers examined tissue from the brain and spinal cord extracted when the disease was at different stages. They used molecular techniques to assess DNA inside neurons and look for any signs of damage. In addition, they looked for molecular markers of parthanatos, such as proteins known to play a role in the fragmentation of DNA.
“In EAE, we used transcriptomic profiling of brain and spinal cord tissues combined with immune fluorescence to examine signals in neurons and glia at the peak of inflammation and at a late time point,” explained Calabresi.
“We found that neurons undergo immune mediated injury through oxidative stress and exhibited signs of DS DNA damage at the early stages of disease. This suggested that parthanatos, a caspase independent cell death pathway, may be involved. Parthanatos is mediated by the release of PAR into the cytoplasm, where it triggers the release of AIF that binds to MIF and allows MIF to translocate to the nucleus where it acts as a nuclease and kills neurons. This pathway has been described in Parkinson’s Disease by our collaborators, Ted and Valina Dawson, in a Cell paper in 2022.”
The researchers subsequently blocked the final stage of parthanatos using genetic pharmacological approaches to inhibit MIF nuclease activity. MIF nuclease is the enzyme responsible for DNA damage in parthanathos. Remarkably, they found that blocking this enzyme reduced DNA fragmentation, led to the survival of more neurons and significantly lowered the severity of the symptoms presented by mice.
“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.
New route to slow down or prevent neurodegeneration
This study is the first to report that pathanatos arising from neuroinflammation is responsible for a sizable portion of cell death in a mouse model of MS. Future work could try to validate these findings and confirm that they also apply to MS in humans.
“The identification of parthanatos as an immune triggered cell death pathway in MS is entirely novel,” said Calabresi. “Further, our ability to inhibit MIF nuclease activity with transgenic mice and a small molecule inhibitor is novel. This could be a good strategy for treating progressive MS and related neurodegenerative diseases.”
The evidence gathered by Calabresi and his colleagues show that parthanatos and the enzyme MIF nuclease could be promising targets for neuroprotective therapies. Their work could eventually inform the development of new pharmaceutical drugs or genetic interventions that prevent the death of brain cells associated with MS, which could in turn reduce the severity of the symptoms experienced by patients.
“We next plan to examine the longevity of MIF nuclease blockade at later timepoints and seek to understand if there may be overlap with ferroptosis, another related cell death pathway,” added Calabresi.