Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias

Matthews, Rowena G.; Elmore, C. Lee

doi:10.1515/cclm.2007.324

Cited by 20 publications

(23 citation statements)

References 16 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A prior study demonstrated that maintaining Mthfd1 gt/+ mice on a diet deficient in both folate and choline lessened the effect of the mutation on SAM levels relative to Mthfd1 gt/+ mice maintained on a diet with sufficient levels of these nutrients (MacFarlane et al, 2009, 2011). Similar compensatory effects have been reported for mice with mutations in genes that alter other aspects of folate metabolism (Elmore et al, 2007; Matthews and Elmore, 2007). SAM plays an important role as a methyl donor, thus affecting DNA methylation (Ulrey et al, 2005) as well as the metabolism of the catecholamines, serotonin, and acetylcholine (Alpert et al, 2002; Chan et al, 2008; Zhu, 2002), all transmitter systems that project to and modulate neocortical functions (Robbins and Arnsten, 2009).…”

Section: Discussionsupporting

confidence: 77%

Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice

Ash

Jiang

Malysheva

et al. 2013

Neurotoxicology and Teratology

View full text Add to dashboard Cite

Converging evidence suggests that folate-mediated one-carbon metabolism may modulate cognitive functioning throughout the lifespan, but few studies have directly tested this hypothesis. This study examined the separate and combined effects of dietary and genetic manipulations of folate metabolism on neocortical functions in mice, modeling a common genetic variant in the MTHFD1 gene in humans. Mutant (Mthfd1gt/+) and wildtype (WT) male mice were assigned to a folate sufficient or deficient diet at weaning and continued on these diets throughout testing on a series of visual attention tasks adapted from the 5-choice serial reaction time task. WT mice on a deficient diet exhibited impulsive responding immediately following a change in task parameters that increased demands on attention and impulse control, and on trials following an error. This pattern of findings indicates a heightened affective response to stress and/or an inability to regulate negative emotions. In contrast, Mthfd1gt/+ mice (regardless of diet) exhibited attentional dysfunction and a blunted affective response to committing an error. The Mthfd1gt/+ mice also showed significantly decreased expression levels for genes encoding choline dehydrogenase and the alpha 7 nicotinic cholinergic receptor. The effects of the MTHFD1 mutation were less pronounced when combined with a deficient diet, suggesting a compensatory mechanism to the combined genetic and dietary perturbation of folate metabolism. These data demonstrate that common alterations in folate metabolism can produce functionally distinct cognitive and affective changes, and highlight the importance of considering genotype when making dietary folate recommendations.

show abstract

Section: Discussionsupporting

confidence: 77%

Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice

Ash

Jiang

Malysheva

et al. 2013

Neurotoxicology and Teratology

View full text Add to dashboard Cite

show abstract

“…To address this, primers specific for mouse cbs were designed for RT-PCR, which was performed using RNA isolated from mouse neural retina and freshly isolated retinal cells. RNA from liver, which has abundant expression of cbs [16], was used as a positive control. We first tested three primer pairs for cbs using liver and retinal samples.…”

Section: Resultsmentioning

confidence: 99%

“…RNA was isolated also from liver as a positive control [16]. RNA was converted to cDNA using SuperScript II Reverse Transcriptase (Invitrogen, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Cystathionine Beta Synthase Expression in Mouse Retina

Markand¹,

Tawfik²,

Ha³

et al. 2013

Current Eye Research

View full text Add to dashboard Cite

Purpose Cystathionine β-synthase (CBS), a key enzyme in the transsulfuration metabolic pathway, converts homocysteine to cystathionine, which is converted to cysteine required for synthesis of the major retinal antioxidant glutathione (GSH). Enzyme activity assays suggest that CBS is present in human and pig retina, however recent studies reported that CBS is not expressed in mouse retina. We found this species difference puzzling. Given the plethora of studies using mouse retina as a model system, coupled with the importance of GSH in retina, we investigated CBS expression in mouse retina at the molecular and cell biological level. Methods Wildtype (WT) mice or mice lacking the gene encoding CBS (cbs−/−) were used in these studies. RNA and protein were isolated from retinas and liver (positive control) for analysis of cbs gene expression by RT-PCR and CBS protein expression by Western blotting, respectively. CBS was analyzed by immunofluorescence in retinal cryosections and primary retinal cells (ganglion, Müller, RPE). CBS enzyme activity was measured in primary Müller cells. Results RT-PCR revealed robust cbs expression in WT liver, brain and retina. Western blotting detected CBS in retina, brain and liver of WT mice, but not in cbs−/− mice liver. In immunohistochemical studies, CBS was present abundantly in the ganglion cell layer of retina; it was detected also in primary isolations of Müller, RPE and ganglion cells. CBS activity was detected in Müller cells by fluorescent detection of H2S. Conclusions We have compelling molecular evidence that CBS is expressed in mouse retina at the gene and protein level. Our immunofluorescence data suggest that it is present in several retinal cell types and the data from the enzyme activity assay suggest activity in Müller cells. These findings set the stage to investigate the role of CBS and the transsulfuration pathway in generation of GSH in mouse retina.

show abstract

“…This complexity confounds the simple interpretation of epidemiological associations between cognitive impairments with folate, homocysteine, and other closely related metabolites and has impeded progress in clarifying the mechanisms that actually account for the epidemiological associations, whatever their theoretical plausibility (4,22,23). …”

Section: Introductionmentioning

confidence: 99%

Cognitive Impairment in Folate-Deficient Rats Corresponds to Depleted Brain Phosphatidylcholine and Is Prevented by Dietary Methionine without Lowering Plasma Homocysteine

Troen

Chao

Crivello

et al. 2008

The Journal of Nutrition

View full text Add to dashboard Cite

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

show abstract

Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias

Cited by 20 publications

References 16 publications

Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice

Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice

Cystathionine Beta Synthase Expression in Mouse Retina

Cognitive Impairment in Folate-Deficient Rats Corresponds to Depleted Brain Phosphatidylcholine and Is Prevented by Dietary Methionine without Lowering Plasma Homocysteine

Contact Info

Product

Resources

About