Variations in p21 protein may explain why some MS types progress faster
Study: Targeting it could boost myelin repair, opening new therapeutic avenues
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A 3D rendering shows a large number of human brains within a circle.
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Variations in p21 protein activity may cause poor myelin repair in multiple sclerosis.
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Reduced p21 activity is linked to diminished oligodendrocyte growth, especially in primary progressive multiple sclerosis.
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Targeting p21 could potentially boost myelin repair, offering new therapeutic interventions for multiple sclerosis.
Variations in the activity of a protein called p21 may underlie the differences in the activity of myelin-repairing cells in the brains of people with multiple sclerosis (MS), according to a new study.
The findings may help to explain why different people with MS develop different forms of the disease, researchers wrote.
“Our findings demonstrate that in MS, inherent deficits in the p21 pathway may alter [brain] cell populations and may contribute to the [development] and clinical manifestations of the disease,” the scientists wrote.
The study, “Impaired myelination in multiple sclerosis organoids: p21 links oligodendrocyte dysfunction to disease subtype,” was published in Frontiers in Cellular Neuroscience. The work was led by scientists at the Tisch MS Research Center of New York, with funding from the center.
Why MS manifests with distinct patterns in different people unclear
Myelin is a fatty substance that wraps around nerve fibers and helps them send electrical signals, somewhat analogous to rubber insulation around a metal wire. In MS, inflammation in the brain and spinal cord damages myelin, disrupting nerve signaling.
Most people with MS initially develop the relapsing-remitting form of the disease, known as RRMS, which is marked by periods of sudden symptom worsening followed by periods of recovery. But about 10% of MS patients instead develop primary progressive MS (PPMS), a disease form characterized by symptoms that gradually worsen over time. Generally, disability progresses much faster in people with PPMS.
It’s long been unclear why MS manifests with distinct patterns in different people, but the new study may help to explain these variations.
In the study, researchers collected blood cells from people with various types of MS and from people without the disease. Using a complex series of biochemical manipulations, the blood cells were turned into cerebral and spinal cord organoids — cell models designed to mimic the 3D architecture of cells in the human nervous system.
Because cells in each organoid retain the donor’s genetic code, this model enabled researchers to examine how inherent genetic variations may influence the growth and activity of brain cells in MS patients.
“These long-term cultured organoids are a novel tool to study the genetic contribution on [brain cell] maturation and myelination capacity, and potentially to better understand the neurodevelopmental aspects of MS,” the researchers wrote.
Oligodendrocyte growth diminished in organoids derived from MS patients
These organoid models included nerve cells and other types of brain cells, such as oligodendrocytes, which are the cells chiefly responsible for producing myelin in the brain and spinal cord.
Results showed that the growth of oligodendrocytes was generally diminished in organoids derived from MS patients, particularly PPMS patients. Impaired oligodendrocyte growth was accompanied by poorer myelin production in the models, the researchers noted.
The decrease in oligodendrocyte growth in MS organoids was also accompanied by reduced activity of p21, a protein that’s key for regulating cell growth. Again, the reduction in p21 signaling was more pronounced in organoids derived from PPMS patients than in those from patients with other MS types.
Our research marks a significant step forward in understanding the reasons for disease progression in PPMS. By identifying how p21 dysregulation affects myelin repair, we open new possibilities for therapeutic interventions that could potentially improve patient outcomes.
Based on their findings, the researchers speculated that inherent genetic variations that influence p21 activity may lead to variations in oligodendrocyte growth — and this, in turn, would give some people less capacity to repair myelin damage, making them more susceptible to the continual damage seen in PPMS.
If that’s true, then it may be possible to boost myelin activity by targeting p21. The researchers stressed, however, that their findings were based on experiments conducted in a single cell model and that further work will be needed to validate and expand on them.
“Our research marks a significant step forward in understanding the reasons for disease progression in PPMS,” Saud A. Sadiq, MD, study co-author and director and chief research scientist of the Tisch MS Research Center of New York, said in a press release from the center. “By identifying how p21 dysregulation affects myelin repair, we open new possibilities for therapeutic interventions that could potentially improve patient outcomes.”
