One-carbon metabolism and schizophrenia: current challenges and future directions

Krebs, Marie‐Odile; Bellon, Alfredo; Mainguy, Gaëll; Jay, Thérèse M.; Frieling, Helge

doi:10.1016/j.molmed.2009.10.001

Cited by 78 publications

(60 citation statements)

References 95 publications

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“…SAM is the methyl donor used by DNMTs to transfer the one carbon methyl group, producing 5-methylcytosine (5mC) and S-adenosylhomocysteine (SAH) in the process (see Figure 2 and Text box 1 for additional details on DNMTs in the brain). The accumulation of homocysteine has been shown to lead to neural damage and cognitive dysfunction (Krebs et al, 2009).…”

Section: Dna Methylationmentioning

confidence: 99%

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

Grayson

Guidotti

2012

Neuropsychopharmacol

244

214

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Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+ ) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures, including multiple mRNAs that are downregulated in both inhibitory GABAergic and excitatory pyramidal neurons compared with non-psychiatric subjects (NPS). Several reports show increased expression of DNA methyltransferases in telencephalic GABAergic neurons. Accumulating evidence suggests a critical role for altered DNA methylation processes in the pathogenesis of SZ and related psychiatric disorders. The establishment and maintenance of CpG site methylation is essential during central nervous system differentiation and this methylation has been implicated in synaptic plasticity, learning, and memory. Atypical hypermethylation of candidate gene promoters expressed in GABAergic neurons is associated with transcriptional downregulation of the corresponding mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent reports indicate that the methylation status of promoter proximal CpG dinucleotides is in a dynamic balance between DNA methylation and DNA hydroxymethylation. Hydroxymethylation and subsequent DNA demethylation is more complex and involves additional proteins downstream of 5-hydroxymethylcytosine, including members of the base excision repair (BER) pathway. Recent advances in our understanding of altered CpG methylation, hydroxymethylation, and active DNA demethylation provide a framework for the identification of new targets, which may be exploited for the pharmacological intervention of the psychosis associated with SZ and possibly BP+ .

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Section: Dna Methylationmentioning

confidence: 99%

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

Grayson

Guidotti

2012

Neuropsychopharmacol

244

214

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Section: Biological Mechanisms Underlying Common Genetic Vulnerabilitmentioning

confidence: 99%

“…MTHFR catalyses the conversion of 5,10-methylenetetrahydrofolate (5,10-MTHF) to 5-MTHF, the predominant circulating form of folate (Frankenburg, 2007;Krebs et al, 2009;Sugden, 2006). 5,10-MTHF is involved in DNA synthesis as an essential donor molecule for purines synthesis and a substrate molecule for thymidine synthase, which is a rate limiting step in DNA biosynthesis (Frankenburg, 2007;Krebs et al, 2009;Sugden, 2006). In the methylation cycle, the methyl group of 5-MTHF is furthermore used for the re-methylation of homocysteine to methionine, and the conversion of methionine to S-adenosylmethionine (SAM), which is a major methyl donor to DNA, proteins, neurotransmitters, hormones and phospholipids (Frankenburg, 2007;Krebs et al, 2009;Sugden, 2006).…”

Section: Biological Mechanisms Underlying Common Genetic Vulnerabilitmentioning

confidence: 99%

“…MTHFR is a crucial enzyme involved in one-carbon metabolism (OCM), a folate-mediated pathway essential for purine and thymidylate biosynthesis, the methylation of DNA and amino acids, and is necessary for reactions forming neurotransmitters (Sugden, 2006). MTHFR and OCM play key roles in physiologic processes by regulating the channeling of onecarbon units between the DNA cycle (nucleotide synthesis) and the methylation cycle (Frankenburg, 2007;Krebs et al, 2009;Laanpere et al, 2010). Dysfunction of the OCM cycle has been linked to neural tube defects (van der Put et al, 2001;Zhang et al, 2008) and autism (Pasca et al, 2009), and may contribute to the pathogenesis of other disorders, including leukemia (de Jonge et al, 2009;Wiemels et al, 2001), dementia (Kim et al, 2008;Kronenberg et al, 2009), colorectal cancer (Kim, 1999;Levine et al, 2010), cardiovascular disease (Smulders and Stehouwer, 2005) and congenital abnormalities (Carmichael et al, 2009;Wani et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: Evidence for a common genetic vulnerability?

Peerbooms

Drukker

et al. 2011

Brain, Behavior, and Immunity

142

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“…Thus, aberrant epigenetic programming during critical periods of fetal development can result in aberrant timing of gene expression and cell differentiation that can heritably alter fetal phenotype (Zeisel 2009). In addition to mediating gene-environment interactions, epigenetic variation in gene expression might help to explain the broad Impaired methionine metabolism has been reproducibly associated with epigenetic dysregulation in several other neurobehavioral disorders (Costa et al 2009;Graff and Mansuy 2009;Grayson et al 2009;Krebs et al 2009). Initial genome-wide epigenetic profiling in individuals with schizophrenia and bipolar disorder revealed DNA methylation changes that mapped to loci involving mitochondrial function, brain development as well as GABAergic and glutamatergic neurotransmission (Mill et al 2008).…”

mentioning

confidence: 99%

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

James¹

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) 2012 REPORT TYPE Final DATES COVERED (From -To) TITLE AND SUBTITLE Redox Abnormalities as a Vulnerability Phenotype for Autism 5a. CONTRACT NUMBERand Related Alterations in CNS Development 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER AUTHOR(S)Sandra Jill James, Ph.D.5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERArkansas Children's Hospital Research Institute Little Rock, AR 72202 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, MD 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; distribution unlimited SUPPLEMENTARY NOTES ABSTRACT:We hypothesize that low systemic redox potential (GSH/GSSG; cysteine/cystine) reflects a vulnerability phenotype that is associated with regressive autism and is predictive of the risk of developing autism. The redox vulnerability phenotype is associated with epigenetic alterations in primary immune cells that may be reversible with restoration of intracellular redox potential. The hypothesis predicts that children with regressive autism and high risk (developmentally-delayed) children who are subsequently diagnosed with autism will exhibit lower redox potential compared to age-matched unaffected control children. It also predicts that low redox potential from these children will be associated with epigenetic modifications in DNA methylation and histone acetylation/methylation that are reversible with treatment to restore redox potential. In Aim 1 we will determine whether redox potential in immune cells can be used as a biomarker for regressive autism and whether it is predictive of the subsequent diagnosis of autism. We will also evaluate immune redox potential from high risk developmentally delayed children to determine whether redox status is predictive of subsequent development of autism. In Aim 2, we will determine whether immune cells from autistic children are associated with altered cytokine patterns,...

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One-carbon metabolism and schizophrenia: current challenges and future directions

Cited by 78 publications

References 95 publications

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: Evidence for a common genetic vulnerability?

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

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