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B12 Deficiency and Multiple Sclerosis Share Intriguing Similarities

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A novel molecular link between vitamin B12 and multiple sclerosis (MS) in astrocytes – important non-neuronal brain cells – has been unearthed in a new study. The research, published in Cell Reports, suggests that brain-targeted B12 formulations may support MS treatment.

The relationship between vitamin B12 and MS

Cobalamin, or vitamin B12, is an essential nutrient that supports a healthy central nervous system (CNS).

People deficient in vitamin B12 can experience symptoms such as muscle weakness, trouble walking, fatigue and increased heart rate.

Interestingly, B12 deficiency can produce neurological symptoms similar to MS, a chronic inflammatory disease of the CNS. Shared symptoms include tingling/numbness in the hands and feet, vision loss and memory problems – but the reasons for this crossover in symptoms have remained unclear.

Now, a team led by Sanford Burnham Prebys researchers has revealed a novel link between vitamin B12 and MS within astrocytes – important non-neuronal brain cells that support the CNS.

B12 pathway is essential for MS drug mechanism

The researchers focused on the effects of the MS drug fingolimod, using both mouse models of MS and post-mortem human brains.

Fingolimod works by suppressing B and T immune cells that mistakenly attack the brain in MS, through modulating the sphingosine 1-phosphate (S1P) receptor highly expressed on the surface of astrocytes.

They found that fingolimod decreases neuroinflammation by regulating vitamin B12 pathways. In astrocytes, fingolimod binding to the S1P receptor (S1P1) elevates levels of a receptor called CD320. This receptor takes up vitamin B12 bound to a carrier protein called TCN2, which distributes B12 around the body, including to the CNS.

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Additionally, the researchers found that dietary restriction of vitamin B12 or low CD320 levels worsened disease in MS mouse models. This also reduced the efficacy of fingolimod, as the drug usually “hitchhikes” its way to the astrocytes by binding to the TCN–B12 complex.

“A molecular link between B12 and MS was identified through a novel CNS mechanism involving astrocytes that potentially explains the controversial relationship between B12 deficiency and MS that has spanned decades without resolution,” the authors write in the paper.

“This was the first report to identify the interactions between fingolimod and the vitamin B12 pathway, especially involving astrocyte CD320,” said senior author Jerold Chun and co-lead author Yasuyuki Kihara, speaking to Technology Networks. “The vitamin B12–TCN2 receptor, CD320, is downregulated in the brains of MS patients: this can then be restored by fingolimod that functionally antagonizes S1P1 and upregulates CD320,” Chun and Kihara explained.

The researchers note that other drugs targeting S1P1 may share parts of this CNS mechanism, and explain that the study supports B12 supplementation with S1P1 modulators to improve their efficacy.

Potential to enhance MS treatments

These new findings support using B12 supplementation to improve the efficacy of fingolimod and other S1P1 modulators, suggesting new ways to improve MS treatment.

“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, a professor in the Center for Genetic Disorders and Aging Research at Sanford Burnham Prebys. “Augmenting brain B12 with fingolimod or potentially related molecules could enhance both current and future MS therapies.”

“It supports creating brain-targeted B12 formulations,” Chun continued. “In the future, this mechanism might also extend to novel treatments of other neuroinflammatory and neurodegenerative conditions.”

Reference: Jonnalagadda D, Kihara Y, Groves A, et al. FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis. Cell Reports. 2023;42(12). doi: 10.1016/j.celrep.2023.113545

This article is a rework of a press release issued by Sandford Burnham Prebys. Material has been edited for length and content.

Dr. Jerold Chun and Dr. Yasuyuki Kihara were speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.