For decades, scientists have been intrigued by the parallels between vitamin B12 deficiency and multiple sclerosis (MS), a chronic autoimmune disease affecting the central nervous system (CNS). Both conditions manifest similar neurological symptoms, prompting researchers to delve into the molecular connections between vitamin B12 and MS.
A recent study, published online on December 7, 2023, in Cell Reports, conducted by researchers at Sanford Burnham Prebys and collaborating institutions, has uncovered a novel molecular link between vitamin B12 and MS, particularly within astrocytes—crucial non-neuronal glial cells in the brain. Vitamin B12, also known as cobalamin, plays a vital role in supporting the healthy development and functioning of the central nervous system.
Its deficiency mirrors the symptoms of MS, including numbness or tingling in extremities, vision loss, difficulties in walking and speaking, and cognitive dysfunction such as memory problems. Recognizing these similarities, the researchers sought to uncover the molecular mechanisms that connect vitamin B12 and MS, with the ultimate goal of enhancing MS treatment through CNS-B12 supplementation.Â
The study, led by senior author Jerold Chun, M.D., Ph.D., and co-corresponding author Yasuyuki Kihara, Ph.D., examined the molecular interactions within astrocytes, focusing on the FDA-approved MS drug fingolimod. Fingolimod, also known as Gilenya, is a sphingosine 1-phosphate (S1P) receptor modulator that suppresses the distribution of T and B immune cells attacking the CNS in MS patients.Â
The researchers found that fingolimod, in an animal model of MS and human post-mortem brains, suppresses neuroinflammation by regulating B12 communication pathways. Specifically, it elevates the B12 receptor CD320, necessary for B12 uptake when bound to transcobalamin 2 (TCN2). TCN2 is the carrier protein that distributes B12 throughout the body, including the CNS. This crucial process, identified for its interactions with fingolimod within astrocytes, was observed in human MS brains as well.Â
Moreover, the study revealed that lower levels of CD320 or dietary B12 restriction worsened the disease course in the animal model of MS and reduced the therapeutic efficacy of fingolimod. Fingolimod, by binding to the TCN2-B12 complex, facilitates the delivery to astrocytes via interactions with CD320. Any disruption in this process exacerbated the disease, emphasizing the intricate interplay between B12, fingolimod, and astrocytes in MS.Â
The findings propose new avenues for enhancing MS treatment through B12 supplementation, particularly in delivering the vitamin to astrocytes within the brain. The study suggests that S1P receptor modulators in addition to fingolimod, such as Mayzent, Zeposia, and Ponvory, may access parts of the CNS mechanism identified in the research. This supports the idea of combining B12 supplementation with S1P receptor modulators to potentially improve drug efficacy for this class of medicines.Â
Additionally, the study unveils insights into the regulation of the B12-TCN2-CD320 pathway by sphingolipids, specifically sphingosine. This naturally occurring compound is an endogenous structural analog of fingolimod. Understanding this regulation could pave the way for developing brain-targeted B12 formulations and novel treatments for other neuroinflammatory and neurodegenerative conditions.Â
The groundbreaking study by Sanford Burnham Prebys researchers has unraveled a crucial link between vitamin B12 and multiple sclerosis, shedding light on the molecular mechanisms within astrocytes. The findings offer a promising avenue for improving MS treatment through CNS-B12 supplementation, potentially enhancing the efficacy of existing drugs like fingolimod.
The study not only advances our understanding of the intricate interplay between B12 and MS but also opens doors to novel treatments for a broader spectrum of neuroinflammatory and neurodegenerative conditions. As research continues in this field, the hope is that these discoveries will translate into innovative therapies, ultimately improving the lives of individuals affected by MS and related disorders.Â
Journal Reference Â
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.2023.113545Â
