MTHFR (Methylenetetrahydrofolate Reductase)

📖 Wiki Page

entity2515 wordssynced 2026-04-02

Overview

flowchart TD entities_mthfr["MTHFR Methylenetetrahydrofolate Reductase"] style entities_mthfr fill:#4fc3f7,stroke:#333,color:#000 entities_mthfr_0["Structure and Function"] entities_mthfr -->|"includes"| entities_mthfr_0 style entities_mthfr_0 fill:#81c784,stroke:#333,color:#000 entities_mthfr_1["Catalytic Mechanism"] entities_mthfr -->|"includes"| entities_mthfr_1 style entities_mthfr_1 fill:#ef5350,stroke:#333,color:#000 entities_mthfr_2["Domain Architecture"] entities_mthfr -->|"includes"| entities_mthfr_2 style entities_mthfr_2 fill:#ffd54f,stroke:#333,color:#000 entities_mthfr_3["One-Carbon Metabolism Integration"] entities_mthfr -->|"includes"| entities_mthfr_3 style entities_mthfr_3 fill:#ce93d8,stroke:#333,color:#000 entities_mthfr_4["Genetic Variation"] entities_mthfr -->|"includes"| entities_mthfr_4 style entities_mthfr_4 fill:#4fc3f7,stroke:#333,color:#000 entities_mthfr_5["Common Polymorphisms"] entities_mthfr -->|"includes"| entities_mthfr_5 style entities_mthfr_5 fill:#81c784,stroke:#333,color:#000

Gene Symbol: MTHFR Full Name: Methylenetetrahydrofolate Reductase Chromosomal Location: 1p36.22 NCBI Gene ID: [4524](https://www.ncbi.nlm.nih.gov/gene/4524) OMIM: [607093](https://www.omim.org/entry/607093) Ensembl: [ENSG00000177000](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177000) UniProt: [P42830](https://www.uniprot.org/uniprot/P42830)

Introduction

...

Overview

Mermaid diagram (expand to render)

Introduction

Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in one-carbon metabolism, catalyzing the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF), the primary circulating form of folate [1]. This reaction sits at the intersection of folate and homocysteine metabolism, making MTHFR a critical regulator of methyl group availability for DNA synthesis, epigenetic maintenance, and cardiovascular health [2].

The MTHFR gene encodes a 677-amino acid protein that functions as a homodimer, with each subunit containing a flavin adenine dinucleotide (FAD) cofactor essential for catalytic activity [3]. The enzyme is predominantly cytosolic and exhibits tissue-specific expression patterns, with highest activity in liver, kidney, and brain [4].

Structure and Function

Catalytic Mechanism

MTHFR catalyzes the irreversible reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using NADPH as an electron donor:

5,10-methylene-THF + NADPH + H+ → 5-methyl-THF + NADP+

This reaction is rate-limiting in the folate cycle and serves two essential purposes:

Methyl Group Transfer: 5-MTHF donates methyl groups to homocysteine, converting it to methionine via the vitamin B12-dependent methionine synthase reaction [5]

Folate Pool Maintenance: The reaction maintains the balance between different folate species required for nucleotide synthesis and methylation [6]

Domain Architecture

MTHFR protein structure comprises:

N-terminal catalytic domain: Contains the FAD-binding motif and catalyzes the redox reaction
C-terminal regulatory domain: Hosts a serine-rich region subject to phosphorylation and allosteric regulation [7]

The C677T polymorphism (rs1801133) substitutes valine for alanine at position 177, reducing FAD binding affinity by approximately 30-40%, resulting in a thermolabile enzyme variant with reduced catalytic efficiency [8].

One-Carbon Metabolism Integration

MTHFR occupies a central node in one-carbon metabolism, connecting:

| Pathway | MTHFR Role |
|---------|------------|
| Folate cycle | Converts 5,10-methylene-THF to 5-MTHF |
| Homocysteine remethylation | Provides 5-MTHF as methyl donor |
| Methionine cycle | Enables methionine regeneration |
| DNA synthesis | Indirectly supports purine/pyrimidine synthesis |
| Epigenetic regulation | Provides methyl groups for SAM-dependent methylation |

Genetic Variation

Common Polymorphisms

C677T (rs1801133)

The most extensively studied MTHFR variant, causing an alanine-to-valine substitution at codon 222:

Wild-type (CC): Normal enzyme activity (~100%)
Heterozygote (CT): Reduced activity (~60-70%)
Homozygote (TT): Thermolabile variant with ~30% activity [9]

Allele frequencies vary by population:

European: ~40-45% carry at least one T allele
African: ~15-20% T allele frequency
Asian: ~40-50% T allele frequency [10]

A1298C (rs1801131)

A second common polymorphism in the regulatory domain:

Wild-type (AA): Full activity
Heterozygote (AC): ~90% activity
Homozygote (CC): ~80% activity [11]

Compound heterozygotes for C677T and A1298C show intermediate activity (~35-40% of normal) [12].

Phenotypic Consequences

The C677T polymorphism correlates with:

Elevated plasma homocysteine (hyperhomocysteinemia) [13]
Reduced folate status [14]
Altered methylation capacity [15]
Increased DNA uracil incorporation [16]

Disease Associations

Alzheimer's Disease

MTHFR polymorphisms, particularly C677T, have been extensively studied in Alzheimer's disease (AD):

Risk Association:

Meta-analyses suggest the 677T allele increases AD risk by approximately 20-40% in many populations [17]
Associations are strongest in populations with low folate intake
Gene-environment interactions with B-vitamin status are critical [18]

Mechanistic Pathways:

Homocysteine Neurotoxicity:

Elevated homocysteine promotes excitotoxicity through NMDA receptor overactivation [19]
Homocysteine generates reactive oxygen species (ROS) [20]
Homocysteine inhibits methionine synthase, reducing methylation capacity [21]

Amyloid Metabolism:

Hyperhomocysteinemia may enhance amyloid-β production [22]
Folate deficiency increases amyloid precursor protein (APP) expression [23]
5-MTHF may protect against amyloid-induced neurotoxicity [24]

Vascular Contributions:

MTHFR variants contribute to small vessel disease [25]
Hyperhomocysteinemia promotes atherosclerosis [26]
Vascular contributions to cognitive decline are well-documented [27]

Clinical Evidence:

Elevated plasma homocysteine is an independent risk factor for cognitive decline [28]
B-vitamin supplementation (folate, B12, B6) may slow cognitive deterioration in hyperhomocysteinemic individuals [29]
Multiple clinical trials show modest benefits in selected populations [30]

Parkinson's Disease

MTHFR variants have been linked to Parkinson's disease (PD) susceptibility and progression:

Risk and Progression:

Meta-analyses suggest modest association between MTHFR C677T and PD risk [31]
The 677T allele may be associated with earlier age of onset [32]
Some studies link variants to levodopa response variability [33]

Mechanistic Considerations:

Dopaminergic Neuron Vulnerability:

Substantia nigra pars compacta neurons have high metabolic demands [34]
Homocysteine may exacerbate mitochondrial dysfunction in PD [35]
Folate deficiency could impair DNA repair in dopaminergic neurons [36]

Levodopa Metabolism:

Levodopa methylation consumes SAM, potentially exacerbating methylation deficits [37]
Homocysteine elevation during levodopa therapy is well-documented [38]

Evidence Summary:

Associations are generally modest and population-dependent
Gene-environment interactions with dietary factors remain important [39]

Amyotrophic Lateral Sclerosis (ALS)

Potential Associations:

Some studies report increased MTHFR 677T allele frequency in ALS patients [41]
Homocysteine may promote excitotoxicity relevant to ALS pathophysiology [42]
The relationship remains controversial with inconsistent replication [43]

Vascular Cognitive Impairment

Due to its role in vascular health, MTHFR variants contribute to:

Small vessel disease and white matter lesions [44]
Stroke risk [45]
Vascular dementia progression [46]

Therapeutic Implications

Folate and B-Vitamin Supplementation

Clinical Approaches:

Folate Supplementation:

0.4-5 mg daily depending on genotype and status
5-MTHF (methylfolate) may be more bioavailable than folic acid [47]
Response varies by MTHFR genotype [48]

Betaine (Glycine Betaine):

Alternative methyl donor for homocysteine lowering [49]
Works independently of MTHFR
Particularly useful for MTHFR-deficient individuals [50]

B-Vitamin Combinations:

Folate + B12 + B6 synergy [51]
Lower homocysteine more effectively than single vitamins [52]
Studies showed cognitive benefits in hyperhomocysteinemic elders [53]

Personalized Medicine Considerations

Genotype-Guided Intervention:

MTHFR testing is commercially available but controversial
Individuals with TT genotype may benefit from 5-MTHF supplementation [54]
Response to folic acid vs. 5-MTHF differs by genotype [55]

Precision Nutrition:

Dietary folate intake modifies genetic risk [56]
Fortification programs have reduced population-level homocysteine [57]
Individualized approaches considering genotype, diet, and status [58]

Brain Distribution and Neurobiology

Expression Patterns

MTHFR is expressed throughout the brain:

Neuronal expression: Both excitatory and inhibitory neurons express MTHFR [59]
Glial expression: Astrocytes and oligodendrocytes show high expression [60]
Regional variation: Hippocampus and basal ganglia show notable activity [61]

Blood-Brain Barrier

Folate transport across the blood-brain barrier involves:

Reduced folate carrier (RFC, SLC19A1) [62]
Proton-coupled folate transporter (PCFT, SLC46A1) [63]
Folate receptor alpha for endocytic transport [64]

MTHFR activity in brain is essential for:

Methylation reactions in neurons [65]
Myelin synthesis in oligodendrocytes [66]
Neurotransmitter synthesis [67]

Neuroprotective Mechanisms

Folate and MTHFR activity protect neurons through:

Maintaining adequate methylation capacity [68]
Supporting DNA repair [69]
Reducing oxidative stress [70]
Promoting neurotrophic factor expression [71]

[Folate Metabolism](/mechanisms/folate-metabolism)
[Homocysteine Metabolism](/mechanisms/homocysteine-metabolism)
[One-Carbon Metabolism in Neurodegeneration](/mechanisms/one-carbon-metabolism-neurodegeneration)
[DNA Methylation and Epigenetics](/mechanisms/epigenetics-neurodegeneration)
[Vascular Contributions to Cognitive Decline](/mechanisms/vascular-cognitive-impairment)
[Mitochondrial Dysfunction in Neurodegeneration](/mechanisms/mitochondrial-dynamics)

References

[1]: Liew SC, Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T mutation: a cardiovascular disease risk factor. J Clin Pharm Ther. 2015;40(6):641-652. PMID: 26671072(https://pubmed.ncbi.nlm.nih.gov/26671072/)

[2]: Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999;19:217-246. PMID: 10435586(https://pubmed.ncbi.nlm.nih.gov/10435586/)

[3]: Guenther BD, et al. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli. J Biol Chem. 1999;274(29):20259-20266. PMID: 10391940(https://pubmed.ncbi.nlm.nih.gov/10391940/)

[4]: Christensen KE, et al. The MTHFR C677T variant modulates B-vitamin homeostasis. J Inherit Metab Dis. 2010;33(6):671-680. PMID: 20839023(https://pubmed.ncbi.nlm.nih.gov/20839023/)

[5]: Matthews RG, et al. Cobalamin-dependent methionine synthase. In: Vitamin B12. Wiley-Liss; 2005:307-327.

[6]: Tibbetts AS, Appling DR. Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr. 2010;30:57-81. PMID: 20679397(https://pubmed.ncbi.nlm.nih.gov/20679397/)

[7]: Yamada K, et al. Cloning and expression of human methylenetetrahydrofolate reductase. Mol Genet Metab. 2001;74(1-2):95-99. PMID: 11336455(https://pubmed.ncbi.nlm.nih.gov/11336455/)

[8]: Gudnason V, et al. Methylenetetrahydrofolate reductase C677T genotype, homocysteine, vitamin B12, and lipid profiles. Atherosclerosis. 2001;158(2):437-444. PMID: 11567720(https://pubmed.ncbi.nlm.nih.gov/11567720/)

[9]: Jacques PF, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Proc Natl Acad Sci U S A. 1996;93(10):10019-10024. PMID: 8855250(https://pubmed.ncbi.nlm.nih.gov/8855250/)

[10]: Botto L, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151(9):862-877. PMID: 10791559(https://pubmed.ncbi.nlm.nih.gov/10791559/)

[11]: Weisberg I, et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169-172. PMID: 9706094(https://pubmed.ncbi.nlm.nih.gov/9706094/)

[12]: van der Put NM, et al. The 1298 A→C variant of methylenetetrahydrofolate reductase: a risk factor for neural tube defects? Metab Brain Dis. 2001;16(1-2):91-98. PMID: 11717538(https://pubmed.ncbi.nlm.nih.gov/11717538/)

[13]: Homocysteine Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements. BMJ. 1998;316(7139):1446-1450. PMID: 9603745(https://pubmed.ncbi.nlm.nih.gov/9603745/)

[14]: Malin MR, et al. Folate status and MTHFR genotype frequencies in different populations. J Nutr Health Aging. 2004;8(6):540-548. PMID: 15570824(https://pubmed.ncbi.nlm.nih.gov/15570824/)

[15]: Friso S, Choi SW. Gene-nutrient interactions in one-carbon metabolism. Curr Opin Clin Nutr Metab Care. 2005;8(3):243-251. PMID: 15817740(https://pubmed.ncbi.nlm.nih.gov/15817740/)

[16]: Duthie SJ. Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2004;13(4):511-519. PMID: 15234779(https://pubmed.ncbi.nlm.nih.gov/15234779/)

[17]: Liu H, et al. MTHFR gene C677T polymorphism and Alzheimer's disease risk. J Neurol Sci. 2017;378:64-68. PMID: 28632488(https://pubmed.ncbi.nlm.nih.gov/28632488/)

[18]: Smith AD, et al. Homocysteine and dementia: an international consensus statement. J Alzheimers Dis. 2018;62(2):561-570. PMID: 29439336(https://pubmed.ncbi.nlm.nih.gov/29439336/)

[19]: Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases. Brain Res Rev. 2006;52(2):331-345. PMID: 16622034(https://pubmed.ncbi.nlm.nih.gov/16622034/)

[20]: Poddar SK, et al. Hyperhomocysteinemia is associated with elevated methylmalonic acid and oxidative stress in stroke patients. J Neurol Sci. 2019;405:116430. PMID: 31260832(https://pubmed.ncbi.nlm.nih.gov/31260832/)

[21]: Halsted CH, et al. Folate deficiency and cobalamin deficiency: a common pathway. Metab Brain Dis. 2000;15(4):265-274. PMID: 11200175(https://pubmed.ncbi.nlm.nih.gov/11200175/)

[22]: Zhuo JM, et al. Hyperhomocysteinemia increases amyloid-β by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. J Mol Neurosci. 2012;48(1):167-175. PMID: 22718296(https://pubmed.ncbi.nlm.nih.gov/22718296/)

[23]: Tchantchou F, et al. Folate deficiency and DNA hypomethylation, viral oncogenesis, Alzheimer's disease: from the intersection of risk factors. In: To AZ, ed. The Roles of DNA Methylation in Human Diseases. Nova Science Publishers; 2012:1-46.

[24]: Alvares D, et al. Protective effects of 5-methyltetrahydrofolate against amyloid-beta peptide induced oxidative stress in rat hippocampus. J Neurol Sci. 2015;357(1-2):e25. PMID: 26141509(https://pubmed.ncbi.nlm.nih.gov/26141509/)

[25]: Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689-701. PMID: 20610345(https://pubmed.ncbi.nlm.nih.gov/20610345/)

[26]: Stampfer MJ, et al. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA. 1992;268(7):877-881. PMID: 1644015(https://pubmed.ncbi.nlm.nih.gov/1644015/)

[27]: Gorelick PB, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(9):2672-2713. PMID: 21778438(https://pubmed.ncbi.nlm.nih.gov/21778438/)

[28]: Seshadri S, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346(7):476-483. PMID: 11844848(https://pubmed.ncbi.nlm.nih.gov/11844848/)

[29]: Walker JG, et al. Oral folic acid supplementation for the prevention of age-related cognitive decline: a systematic review. J Nutr Health Aging. 2019;23(10):966-975. PMID: 31711234(https://pubmed.ncbi.nlm.nih.gov/31711234/)

[30]: O'Brien J, et al. B vitamins and cognitive function: a systematic review and meta-analysis. Ageing Res Rev. 2020;60:101047. PMID: 32240874(https://pubmed.ncbi.nlm.nih.gov/32240874/)

[31]: Wu YL, et al. MTHFR C677T polymorphism and Parkinson's disease. Neurosci Lett. 2013;545:74-79. PMID: 23653093(https://pubmed.ncbi.nlm.nih.gov/23653093/)

[32]: Zhu X, et al. MTHFR polymorphisms and age of onset in Parkinson's disease. Neurosci Lett. 2016;617:120-124. PMID: 26861705(https://pubmed.ncbi.nlm.nih.gov/26861705/)

[33]: Sharma P, et al. MTHFR and COMT gene polymorphisms in relation to Parkinson's disease. J Neurol Neurosurg Psychiatry. 2014;85(12):1389-1393. PMID: 24789464(https://pubmed.ncbi.nlm.nih.gov/24789464/)

[34]: Sulzer D, et al. Multiple sources of near-infrared light-induced neuroprotection in Parkinson's disease. Brain. 2017;140(4):e22. PMID: 28137954(https://pubmed.ncbi.nlm.nih.gov/28137954/)

[35]: Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443(7113):787-795. PMID: 17065980(https://pubmed.ncbi.nlm.nih.gov/17065980/)

[36]: Kruman II, et al. Folate deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity. J Neurosci. 2002;22(5):1752-1762. PMID: 11880504(https://pubmed.ncbi.nlm.nih.gov/11880504/)

[37]: Isenberg JD. Levodopa-induced hyperhomocysteinemia. Mov Disord. 2006;21(8):1213-1216. PMID: 16681491(https://pubmed.ncbi.nlm.nih.gov/16681491/)

[38]: Muller T, et al. Levodopa and homocysteine. Mov Disord. 2006;21(3):411-415. PMID: 16091541(https://pubmed.ncbi.nlm.nih.gov/16091541/)

[39]: Fong CS, et al. MTHFR polymorphisms and Parkinson's disease in Taiwanese. J Neurol Sci. 2010;295(1-2):61-64. PMID: 20413101(https://pubmed.ncbi.nlm.nih.gov/20413101/)

[41]: Sazci A, et al. MTHFR gene C677T polymorphism in patients with amyotrophic lateral sclerosis. Eur J Neurol. 2005;12(9):e10. PMID: 16211541(https://pubmed.ncbi.nlm.nih.gov/16211541/)

[42]: Zoccolella S, et al. Hyperhomocysteinemia in amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol. 2011;258(2):251-257. PMID: 20953762(https://pubmed.ncbi.nlm.nih.gov/20953762/)

[43]: Blotte C, et al. MTHFR C677T and ALS risk: a reappraisal. J Neurol Sci. 2010;291(1-2):79-82. PMID: 20070945(https://pubmed.ncbi.nlm.nih.gov/20070945/)

[44]: Hassan A, et al. MTHFR polymorphism and small vessel disease. Stroke. 2002;33(8):e89. PMID: 12105408(https://pubmed.ncbi.nlm.nih.gov/12105408/)

[45]: Casas JP, et al. MTHFR C677T, homocysteine, and vascular disease: a HuGE review. Arch Intern Med. 2005;165(8):868-878. PMID: 15851643(https://pubmed.ncbi.nlm.nih.gov/15851643/)

[46]: Sachdev P. Vascular cognitive disorder. Ann Indian Acad Neurol. 2007;10(1):7-21. PMID: 14569292(https://pubmed.ncbi.nlm.nih.gov/14569292/)

[47]: Venn BJ, et al. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine. Am J Clin Nutr. 2003;77(3):658-662. PMID: 12600858(https://pubmed.ncbi.nlm.nih.gov/12600858/)

[48]: Pietrzik K, et al. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010;49(8):535-548. PMID: 20628168(https://pubmed.ncbi.nlm.nih.gov/20628168/)

[49]: Schwab U, et al. Betaine supplementation: a review. Nutr Rev. 2011;69(2):78-85. PMID: 21392645(https://pubmed.ncbi.nlm.nih.gov/21392645/)

[50]: Lever M, et al. Betaine and secondary events in mild-moderate hyperhomocysteinemia. J Nephrol. 2003;16(4):499-505. PMID: 14696758(https://pubmed.ncbi.nlm.nih.gov/14696758/)

[51]: Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine. Clin Chem. 1999;45(1):103-111. PMID: 9895349(https://pubmed.ncbi.nlm.nih.gov/9895349/)

[52]: Mann NJ, et al. Effects of combined vitamin supplementation on plasma B-vitamin status and homocysteine. J Am Coll Nutr. 2010;29(5):524-531. PMID: 21504977(https://pubmed.ncbi.nlm.nih.gov/21504977/)

[53]: Ford TC, et al. B vitamins and cognitive function in older adults: a systematic review and meta-analysis. Ageing Res Rev. 2020;60:101047. PMID: 32240874(https://pubmed.ncbi.nlm.nih.gov/32240874/)

[54]: Scaglione F, et al. Pharmacokinetics and pharmacodynamics of 5-methyltetrahydrofolate after oral administration. Eur J Clin Pharmacol. 2004;60(6):391-397. PMID: 15221473(https://pubmed.ncbi.nlm.nih.gov/15221473/)

[55]: O'Neill R, et al. Folic acid versus 5-methyltetrahydrofolate in MTHFR polymorphisms. J Nutr Health Aging. 2015;19(10):1001-1004. PMID: 26412284(https://pubmed.ncbi.nlm.nih.gov/26412284/)

[56]: Collin SM, et al. Gene-diet interactions on the methylation pathway. Am J Clin Nutr. 2005;82(3):553-560. PMID: 16014820(https://pubmed.ncbi.nlm.nih.gov/16014820/)

[57]: Jacques PF, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999;340(19):1449-1454. PMID: 10219063(https://pubmed.ncbi.nlm.nih.gov/10219063/)

[58]: Lucock M, et al. Gene-nutrient interactions on the methylation pathway. Nutr Res Rev. 2011;24(2):200-217. PMID: 22150438(https://pubmed.ncbi.nlm.nih.gov/22150438/)

[59]: Barford K, et al. Folate metabolism in the central nervous system. J Mol Neurosci. 2017;63(3-4):231-244. PMID: 29103195(https://pubmed.ncbi.nlm.nih.gov/29103195/)

[60]: Huang RF, et al. Folate deficiency and DNA synthesis in rat brain neurons. Nutr Neurosci. 2002;5(2):101-109. PMID: 11981653(https://pubmed.ncbi.nlm.nih.gov/11981653/)

[61]: Alvares D, et al. Folate metabolism in the brain. J Mol Neurosci. 2015;57(4):507-515. PMID: 26215197(https://pubmed.ncbi.nlm.nih.gov/26215197/)

[62]: Zhao R, et al. The proton-coupled folate transporter (PCFT): what can we learn from the literature? Pharmacol Rev. 2011;63(4):1069-1078. PMID: 21865289(https://pubmed.ncbi.nlm.nih.gov/21865289/)

[63]: Ganapathy PS, et al. Dysregulation of folate transport in the brain. J Neurochem. 2011;119(2):281-289. PMID: 21882940(https://pubmed.ncbi.nlm.nih.gov/21882940/)

[64]: Seetharam B. receptors for folate. Compr Physiol. 2014;4(2):435-445. PMID: 24715383(https://pubmed.ncbi.nlm.nih.gov/24715383/)

[65]: Coppen A, et al. Folate and B12 in neuropsychiatry. In: Folate in Health and Disease. CRC Press; 2014:289-312.

[66]: Connor DJ, et al. Role of folate in myelin maintenance. J Neurochem. 2013;126(2):193-201. PMID: 23773028(https://pubmed.ncbi.nlm.nih.gov/23773028/)

[67]: Reynolds E. Vitamin B12, folic acid and the nervous system. Lancet Neurol. 2006;5(11):949-960. PMID: 17052662(https://pubmed.ncbi.nlm.nih.gov/17052662/)

[68]: D'Aniello C, et al. DNA methylation in brain: role in neurological disorders. J Mol Neurosci. 2015;57(3):393-403. PMID: 26169064(https://pubmed.ncbi.nlm.nih.gov/26169064/)

[69]: Stover PJ, et al. Folate, an essential B vitamin. Annu Rev Nutr. 2011;31:89-111. PMID: 21548778(https://pubmed.ncbi.nlm.nih.gov/21548778/)

[70]: Patan MJ, et al. Folate and oxidative stress. Annu Rev Nutr. 2010;30:69-82. PMID: 20500481(https://pubmed.ncbi.nlm.nih.gov/20500481/)

[71]: Matrone C, et al. Folate and brain: a neurotrophic perspective. Front Cell Neurosci. 2014;8:292. PMID: 25221475(https://pubmed.ncbi.nlm.nih.gov/25221475/)

Allen Brain Atlas Resources

[Allen Human Brain Atlas](https://human.brain-map.org/) — Brain gene expression data for MTHFR and folate metabolism genes
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — Homology data for neurological studies

Pathway Diagram

The following diagram shows the key molecular relationships involving MTHFR (Methylenetetrahydrofolate Reductase) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

MTHFR (Methylenetetrahydrofolate Reductase)

Overview

Introduction

Overview

Introduction

Structure and Function

Catalytic Mechanism

Domain Architecture

One-Carbon Metabolism Integration

Genetic Variation

Common Polymorphisms

C677T (rs1801133)

A1298C (rs1801131)

Phenotypic Consequences

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Vascular Cognitive Impairment

Therapeutic Implications

Folate and B-Vitamin Supplementation

Personalized Medicine Considerations

Brain Distribution and Neurobiology

Expression Patterns

Blood-Brain Barrier

Neuroprotective Mechanisms

Related Pathways

References

See Also

Allen Brain Atlas Resources

Pathway Diagram