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Progressive multiple sclerosis: the role of cellular senescence

Some chronic neurodegenerative white matter diseases, first and foremost progressive multiple sclerosis (MS), are characterized by loss of myelin, the sheath that covers neuronal axons and is produced by oligodendrocytes, along with progressive axonal degeneration and loss. This is responsible for severe motor and sensory deficits. By studying oligodendrocytes, a group of researchers at San Raffaele – led by Stefano Previtali, head of the Neuromuscular Repair Laboratory at IRCCS Ospedale San Raffaele – has uncovered a completely new pathogenic mechanism that could help to understand how progressive multiple sclerosis develops and progresses.

According to their results, recently published in the Journal of Clinical Investigation, cellular senescence could be the mechanism sustaining demyelination, inflammation and neurodegeneration typical of progressive MS..

The study was possible thanks to the support of the Italian Multiple Sclerosis Association (FISM).

A new model for progressive multiple sclerosis

“Due to their function, i.e. to produce myelin, oligodendrocytes are cells with a fundamental role in both the development and the treatment of demyelinating diseases,” explains Cristina Rivellini, first author of the study. “We identified a protein – JAB1 – that has a key role in protecting oligodendrocytes from DNA damage and oxidative stress, ensuring their correct functioning.”

To test this hypothesis, San Raffaele researchers first created an experimental animal model lacking the expression of JAB1 in oligodendrocytes. The absence of the protein quickly resulted in a progressive demyelination of the central nervous system.

“In addition to demyelination, we also observed neurodegeneration and increased microglia inflammation, which represent the first and main immune defense of the central nervous system. These are all features that are found in human progressive MS, and that until now we were not able to replicate in a single experimental model,” Previtali specifies.

The role of cellular senescence

JAB1 protein was already known to be involved in a number of key cellular processes: depending on the organ or tissue, its absence or reduced functionality can lead to different types of dysfunctions and even cellular apoptosis.

“We noticed that oligodendrocytes lacking JAB1 expression do not die, on the contrary, they resist and develop senescence: this means that, although alive, they release inflammatory molecules and can no longer perform their original tasks, in this case producing myelin. This leads not only to demyelination, but subsequently to inflammation and neurodegeneration”.

By genetically interfering with the senescence process, researchers successfully slowed down the onset of the disease. The study suggests that senescence may be one of the key mechanisms underlying neurodegeneration and may be a potential new therapeutic target.

“By targeting JAB1, we were able to reproduce the clinical and pathological features of progressive MS in the laboratory and to identify a novel mechanism underlying neurodegeneration and inflammation in progressive MS: cellular senescence,” Previtali concludes. “The next step is to find effective and safe strategies to counteract it, in the hope it could slow down disease onset or progression.”