#ACTRIMS2022 – Blocking Fibulin-2 Protein May Increase Remyelination

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A matrix protein called fibulin-2, which is increased in multiple sclerosis (MS) lesions, blocks the activity of oligodendrocytes, the cells responsible for making myelin.

Blocking this protein may be a promising approach to restore myelin in people with the neurodegenerative disease, a study in mice showed.

The data was presented by Samira Ghorbani, PhD, a postdoctoral researcher at the University of Calgary, in Canada, at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022. Her talk was titled “Fibulin-2 as a potent extracellular matrix inhibitor of remyelination in MS.”

MS is caused by an erroneous immune attack against the myelin sheath, a layer of fatty molecules that surrounds nerve fibers and helps them send electrical signals. When myelin is damaged, cells called oligodendrocytes have the capacity to make new myelin — a process termed remyelination. However, remyelination is inefficient in MS patients.

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The extracellular matrix, or ECM, is a collection of proteins and other molecules that surrounds cells in tissues, helping to give the tissue its structure and keeping all of the cells in their proper place. The ECM is abnormal in MS, and this is thought to contribute to inefficient remyelination.

Fibulin-2 is “among the most [overly produced] ECM members” in MS, according to Ghorbani. In MS, supportive brain cells called astrocytes make excessive amounts of this protein following inflammatory brain injury. However, the functional consequences of fibulin-2 upregulation are unclear.

“Our question was: Does fibulin-2 affect oligodendrocytes and remyelination?” Ghorbani said.

To answer this, the researchers engineered mice that were unable to produce fibulin-2 in their astrocytes, and compared them with normal, or wild-type mice. Both animal groups were induced to develop experimental autoimmune encephalitis (EAE), a condition that models MS.

Results demonstrated that, broadly, mice lacking fibulin-2 had less severe disease than their wild-type counterparts, particularly during the chronic phase of the disease.

Based on the results, Ghorbani concluded that “loss of fibulin-2 in astrocytes results in better recovery” from MS-like disease.

Further tissue analyses showed that mice lacking the fibulin-2 protein had increased numbers of oligodendrocytes in their brains. In cell experiments, growing oligodendrocytes in the presence of fibulin-2 also decreased the number of these cells and delayed the production of myelin sheaths, further suggesting that the protein interferes with the growth of these myelin-making cells.

Through additional experiments, the researchers determined that fibulin-2 interferes with the transition from early, immature precursor cells — aptly called pre-oligodendrocytes — through mature oligodendrocytes that can produce myelin.

Fibulin-2 specifically caused the cells to die by activating an inhibitory pathway called Notch. Apoptosis, a form of programmed cell death, also was activated by fibulin-2.

Of note, the researchers demonstrated that the structure of fibulin-2 is physically similar to a signaling protein called Jagged that normally activates the Notch receptors. This is presumably why fibulin-2 activates the Notch signaling pathway.

Taken together, these data suggest that increased levels of fibulin-2 in the ECM in people with MS activate the Notch pathway in developing oligodendrocytes, killing these cells and ultimately interfering with remyelination.

The results indicate that blocking either fibulin-2 or Notch signaling could help to promote remyelination — ultimately easing the disease. The researchers are currently working to understand exactly which part of the fibulin-2 protein is needed to activate Notch receptors, which is a first step toward finding therapies that block this interaction.

“Overcoming [fibulin-2] has the therapeutic potential to improve remyelination and prognosis in MS,” the team concluded.

 

Editor’s note: The Multiple Sclerosis News Today team is providing in-depth coverage of the ACTRIMS Forum 2022 Feb. 24–26. Go here to see the latest stories from the conference.

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