by Sanford-Burnham Prebys

Credit: Cell Reports (2023). DOI: 10.1016/j.celrep.2023.113545

For decades, scientists have noted an intriguing similarity between a deficiency in vitamin B₁₂—an essential nutrient that supports healthy development and functioning of the central nervous system (CNS)—and multiple sclerosis (MS), a chronic disease in which the body's immune system attacks the CNS and which can produce neurodegeneration.

Both vitamin B₁₂ (also known as cobalamin) deficiency and MS produce similar neurological symptoms, including numbness or tingling in hands and feet, vision loss, difficulty walking or speaking normally and cognitive dysfunction, such as problems with memory.

In a new study, published online December 7, 2023 in Cell Reports, researchers at Sanford Burnham Prebys, with collaborators elsewhere, describe a novel molecular link between vitamin B₁₂ and MS that takes place in astrocytes—important non-neuronal glial cells in the brain.

The findings by senior study author Jerold Chun, M.D., Ph.D., professor and senior vice president of neuroscience drug discovery, and Yasuyuki Kihara, Ph.D., research associate professor and co-corresponding author, and colleagues suggest new ways to improve the treatment of MS through CNS-B₁₂ supplementation.

"The shared molecular binding of the brain's vitamin B₁₂ carrier protein, known as transcobalamin 2 or TCN2, with the FDA-approved MS drug fingolimod provides a mechanistic link between B₁₂ signaling and MS, towards reducing neuroinflammation and possibly neurodegeneration," said Chun.

"Augmenting brain B₁₂ with fingolimod or potentially related molecules could enhance both current and future MS therapies."

In their paper, the team at Sanford Burnham Prebys, with collaborators at University of Southern California, Juntendo University in Japan, Tokyo University of Pharmacy and Life Sciences and State University of New York, focused on the molecular functioning of FTY720 or fingolimod (Gilenya), a sphingosine 1-phosphate (S1P) receptor modulator that suppresses distribution of T and B immune cells errantly attacking the brains of MS patients.

Working with an animal model of MS as well as human post-mortem brains, the researchers found that fingolimod suppresses neuroinflammation by functionally and physically regulating B₁₂ communication pathways, specifically elevating a B₁₂ receptor called CD320 needed to take up and use needed B₁₂ when it is bound to TCN2, which distributes B₁₂ throughout the body, including the CNS. This known process was newly identified for its interactions with fingolimod within astrocytes. Importantly, the relationship was also observed in human MS brains.

Of particular note, the researchers reported that lower levels of CD320 or dietary B₁₂ restriction worsened the disease course in an animal model of MS and reduced the therapeutic efficacy of fingolimod, which occurred through a mechanism in which fingolimod hitchhikes by binding to the TCN2-B₁₂ complex, allowing delivery of all to the astrocytes via interactions with CD320, with component losses disrupting the process and worsening disease.

More information: Deepa Jonnalagadda et al, FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis, Cell Reports (2023). DOI: 10.1016/j.celrep.2023.113545

Journal information: Cell Reports 

Provided by Sanford-Burnham Prebys