Neuropathology of vitamin B₁₂deficiency in theCd320^−/−mouse

Abstract

In humans, vitamin B12 deficiency causes peripheral and CNS manifestations. Loss of myelin in the peripheral nerves and the spinal cord (SC) contributes to peripheral neuropathy and motor deficits. The metabolic basis for the demyelination and brain disorder is unknown. The transcobalamin receptor–knockout mouse (Cd320−/−) develops cobalamin (Cb1) deficiency in the nervous system, with mild anemia. A decreased S‐adenosylme‐thionine:S‐adenosylhomocysteine ratio and increased methionine were seen in the brain with no significant changes in neurotransmitter metabolites. The structural pathology in the SC presented as loss of myelin in the axonal tracts with inflammation. The sciatic nerve (SN) showed increased nonuniform, internodal segments suggesting demyelination, and remyelination in progress. Consistent with these changes, the Cd320−/− mouse showed an increased latency to thermal nociception. Further, lower amplitude of compound action potential in the SN suggested that the functional capacity of the heavily myelinated axons were preferentially compromised, leading to loss of peripheral sensation. Although the metabolic basis for the demyelination and the structural and functional alterations of the nervous system in Cb1 deficiency remain unresolved, the Cd320−/− mouse provides a unique model to investigate the pathologic consequences of vitamin B12 deficiency.—Arora, K., Sequeira, J. M., Alarcon, J. M., Wasek, B., Arning, E., Bottiglieri, T., Quadros, E. V. Neuropathology of vitamin B12 deficiency in the Cd320−/− mouse. FASEB J. 33, 2563–2573 (2019). http://www.fasebj.org

Vitamin B12 Deficiency Dysregulates m6A mRNA Methylation of Genes Involved in Neurological Functions

“…[41] We tested FTO expression in the hippocampus, as it is the cerebral substructure that is the most impacted by vitamin B 12 deficiency in the Cd320 knock-out model. [8,9] We did not detect any change of its expression in the hippocampus of adult knock-out mice, nor in the hypothalamus (data not shown). This finding in the brain of Cd320 −/− mice contrasted with the overexpression of FTO found in the two cellular models.…”

“…However, ratio, demyelination in the spinal cord and sciatic nerves, and defects in hippocampal-dependent learning and memory. [8][9][10] At the molecular level, vitamin B 12 deficiency results in increased stress of the endoplasmic reticulum through a reduced expression of SIRT1, which could be explained by a mislocalization of the nuclear ELAVL1/HuR RNA-binding protein (RBP). [11][12][13] This altered localization of RBP was also reported for alternative splicing factors such as hnRNPA1 or RBM10 [13] and likely participates in the genomic changes observed in B 12 deprived cells that control brain development, neuroplasticity, or myelin formation.…”

Disrupting microglial TGF-β signaling triggers region-specific pathology in the spinal cord

“…Detailed characterization would be needed to provide more solid evidence, and it would add more value if similar findings could be recapitulated in human spinal cords. Human neurological diseases such as copper deficiency myelopathy and subacute combined degeneration primarily exhibit degenerative pathologies in the dorsal column of the spinal cord [125][126][127][128][129] , with accumulation of foamy microglia 130,131 . It would be of interest to investigate the involvement of dysregulated microglial TGF-β signaling in these human diseases.…”

Influence of the brain‑gut axis on neuroinflammation in cerebral ischemia‑reperfusion injury (Review)

“…Deficiencies in both VB12 and folic acid have been linked to heightened stroke risk ( 111 ). As VB12 is essential for fatty acid synthesis in the citric acid-pyruvic acid cycle, its absence can impede the recuperation of myelinated nerve fibers post-ischemic events ( 112 ). Homocysteine (Hcy) is converted into methionine through the enzyme methionine synthase.…”