Investigating a unique role for vitamin B12 in oligodendrocyte lipid homeostasis and its relevance to white matter pathology
Active Project Grant Awarded Last action
- Award ID
- F32NS148705
- Recipient
-
The Salk Institute For Biological Studies. San Diego. California UEI NNJ6BMBTFGN5
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $78,450
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 0% complete
- Place of performance
- La Jolla, CA 92037, USA
Award details come from USAspending.gov.
Description
- Abstract
- Oligodendrocytes (OLS) possess unique metabolic requirements to generate and maintain lipid-rich myelin that enables efficient propagation of electrical signals in the central nervous system (CNS). OL metabolic dysfunction is thought to contribute to neurological disease, however, the fundamental principles governing OL metabolism and the mechanisms by which IT becomes dysfunctional remain unclear. Preliminary data reveal that primary mouse OLS exhibit a marked sensitivity to vitamin B12 deficiency compared to other brain cells, resulting in the abnormal accumulation of ODD-chain fatty acids (OCFAS). Adenosylcobalamin (ADOCBL), a bioactive form of vitamin B12, is required as a cofactor for methylmalonyl-coenzyme a (COA) mutase (MUT), a key enzyme in propionate metabolism. ADOCBL deficiency inhibits MUT activity, leading to an upstream build-up of propionyl- COA and OCFAS. Early reports of abnormal ocfa accumulation in neural tissues came from post-mortem analyses of patients with rare inborn errors of vitamin B12 metabolism, but the underlying pathological significance of OCFAS in the CNS is still unknown. Aside from genetic disorders, aging is the biggest risk factor for vitamin B12 deficiency due to gastric malabsorption, and age-related white matter abnormalities are closely linked to cognitive decline and neurological disability. Striking observations from preliminary work indicate that myelin and OLS from aged mice exhibit a distinct ocfa-enriched lipid signature compared to young adult controls. However, despite its effect on lipogenesis, the role of ADOCBL has yet to be studied in OLS. Thus, the overall goal of this proposal is to elucidate the unique, previously unknown requirement for ADOCBL to maintain OL lipid homeostasis and investigate its potential as a novel metabolic mechanism of age-related white matter pathology. Aim 1 will test the hypothesis that age-associated inflammatory factors known to act on ADOCBL can disrupt OL lipogenesis. Specifically, precise flux measurements of OL lipogenic pathways in response to endogenous ADOCBL inhibitors will be generated that cannot be quantified via steady-state metabolomics alone. In aim 2, patch-clamp electrophysiology and electron microscopy analyses of neuron-OL CO-cultures will be performed to test the hypothesis that ocfa enrichment confers altered structural and biochemical properties to the myelin sheath, ultimately causing functional deficits in electrical signaling. Finally, aim 3 will determine if ADOCBL metabolism and MUT activity is altered in OLS of aged mice as a first step in establishing a critical link between the ocfa signature of aged mice and ADOCBL deficiency. The proposed research will better our understanding of the fundamental principles governing OL lipid metabolism and elucidate a potential metabolic basis contributing to age-related white matter pathology. These aims were designed with high training potential to develop the applicant's knowledge and skills in conducting cutting-edge fluxomic analyses both in vitro and in vivo as well as functional neuronal assays to prepare the applicant to make future contributions as an independent investigator in the field of molecular neuroscience.
Quick answers
Who received award F32NS148705?
F32NS148705 was awarded to The Salk Institute For Biological Studies. San Diego. California by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on December 1, 2026.
How much is award F32NS148705 worth?
$78,450 has been obligated on F32NS148705.
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