Altered mannose metabolism in chronic stress and depression is rapidly reversed by vitamin B12

Franzka, Patricia; Turecki, Gustavo; Cubillos, Susana; Kentache, Takfarinas; Steiner, Johann; Walter, Martin; Hübner, Christian A.; Engmann, Olivia

doi:10.3389/fnut.2022.981511

Cited by 8 publications

(3 citation statements)

References 34 publications

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“…To support ACSS2 as a potential therapeutic target, D-mannose was specifically selected as a rapid ACSS2 inducer to mediate fast- and long-acting antidepressant responses. The findings of a previous report support that D-mannose metabolism dysfunction is closely involved in depression patients or mice with depressive-like behaviors and that vitamin B12 can rapidly normalize mannose metabolism to improve chronic stress induced depressive-like behaviors of mice [ 43 ]. Unexpectedly, here, we found that a single gavage of 200 μl 20% D-mannose produced significant reductions in depressive symptoms.…”

Section: Discussionmentioning

confidence: 53%

D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels

Chen,

Zhao,

Guo

et al. 2023

Transl Psychiatry

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The potentiation of synaptic plasticity and serotonin generation by brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (TPH2) is well characterized to facilitate rapid and long-lasting antidepressant actions. Therefore, the identification of the key protein that simultaneously controls both BDNF and TPH2 is important for the treatment of depression. We show here that a lack of acetyl-CoA synthetase short-chain family member 2 (ACSS2) causes impairments in BDNF-dependent synaptic plasticity and tryptophan hydroxylase 2 (TPH2)-mediated serotonin generation, thereby contributing to spontaneous and chronic restraint stress (CRS)-induced depressive-like behavior in mice. Conversely, D-mannose is identified as a rapid ACSS2 inducer and thus mediates rapid and long-lasting antidepressant-like effects. Mechanistically, acute and chronic D-mannose administration inhibits the phosphorylation of EF2 to increase BDNF levels and reverse the reduction of TPH2 histone acetylation and transcription. We reveal that ACSS2 promotes TPH2 histone acetylation and transcription with the requirement of AMPK activation. To elevate nuclear ACSS2 levels, D-mannose can rapidly and persistently activate AMPK via Ca2+-CAMKK2 and the lysosomal AXIN-LKB1 pathway to facilitate its fast-acting and persistent antidepressant responses. Taken together, the results presented here reveal that ACSS2 functions as a novel target to link rapid and persistent antidepressant actions and further suggest that D-mannose is a potential therapeutic agent to resist depression through its augmentation of the ACSS2 dependent BDNF and TPH2 pathways.

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Section: Discussionmentioning

confidence: 53%

D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels

Chen,

Zhao,

Guo

et al. 2023

Transl Psychiatry

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“…Pregnant mother mice or pups were sacrificed and brain as well as skeletal muscle tissue ( musculus quadriceps femoris ) from embryos or pups was isolated. Tissue lysates were prepared as described previously ( Franzka et al, 2022 ). Shortly, samples were homogenized with the Potter S tissue homogenizer (Sartorius) in RIPA buffer [50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1% (v/v) NP-40, 1% (w/v) sodium deoxycholate, 0.1% (w/v) SDS, 1 mM EDTA] and complete protease inhibitor (Roche).…”

Section: Methodsmentioning

confidence: 99%

Consequences of GMPPB deficiency for neuromuscular development and maintenance

Schurig,

Umeh,

Henze

et al. 2024

Front. Mol. Neurosci.

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Guanosine diphosphate-mannose pyrophosphorylase B (GMPPB) catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, which is required as a mannose donor for the biosynthesis of glycan structures necessary for proper cellular functions. Mutations in GMPPB have been associated with various neuromuscular disorders such as muscular dystrophy and myasthenic syndromes. Here, we report that GMPPB protein abundance increases during brain and skeletal muscle development, which is accompanied by an increase in overall protein mannosylation. To model the human disorder in mice, we generated heterozygous GMPPB KO mice using CIRSPR/Cas9. While we were able to obtain homozygous KO mice from heterozygous matings at the blastocyst stage, homozygous KO embryos were absent beyond embryonic day E8.5, suggesting that the homozygous loss of GMPPB results in early embryonic lethality. Since patients with GMPPB loss-of-function manifest with neuromuscular disorders, we investigated the role of GMPPB in vitro. Thereby, we found that the siRNA-mediated knockdown of Gmppb in either primary myoblasts or the myoblast cell line C2C12 impaired myoblast differentiation and resulted in myotube degeneration. siRNA-mediated knockdown of Gmppb also impaired the neuron-like differentiation of N2A cells. Taken together, our data highlight the essential role of GMPPB during development and differentiation, especially in myogenic and neuronal cell types.

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“…Previous research in our team demonstrated that a single acute dose of vitamin B12 reduced depressive-like behaviors in mice in the chronic mild stress (CMS)-model 14 . Additionally, vitamin B12 rescued stress-induced alterations in plasma mannose and Gmppb 15 , a key enzyme of glycosylation metabolism associated with depression 16 . Despite these correlative findings, it is unclear how vitamin B12 mediates stress resilience and improves markers of depression on a molecular level.…”

Section: Introductionmentioning

confidence: 97%

Transthyretin orchestrates vitamin B12-induced stress resilience

Stein,

Aly,

Manzolillo

et al. 2024

Preprint

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Chronic stress significantly contributes to mood- and anxiety disorders. Previous and current data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood. This study reveals a molecular pathway that functionally connects vitamin B12, DNA methylation (DNAme), and stress resilience. We identified Transthyretin (Ttr) as a sex-specific key target of vitamin B12 action in chronic stress. Accordingly,TTRexpression was increased postmortem in the prefrontal cortex of male, but not female, depressed patients. Virally alteredTtrin the prefrontal cortex functionally contributed to stress- and depression-related behaviors, changes in dendritic spine morphology and gene expression. In stressed mice, vitamin B12 reduced DNAme in theTtrpromoter region. Importantly, usingin vivoepigenome editing to alter DNAme in the brains of living mice for the first time, we establish a direct causal link between DNAme onTtrand stress-associated behaviors. In summary, using state-of-the-art techniques, this study uncovers a mechanistic link between cobalamin supplementation and markers of chronic stress and depression, encouraging further studies into environmental interventions for mood disorders.

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Altered mannose metabolism in chronic stress and depression is rapidly reversed by vitamin B12

Cited by 8 publications

References 34 publications

D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels

D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels

Consequences of GMPPB deficiency for neuromuscular development and maintenance

Transthyretin orchestrates vitamin B12-induced stress resilience

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