RARE DISEASE
Disorder of folate metabolism and transport
Disorder of folate metabolism and transport
Disorder of folate metabolism and transport
Drug discovery
0
drugs
With orphan designations
Overview
Disorders of folate metabolism and transport: genetic conditions that impair folate absorption, transport, or intracellular processing, leading to systemic and neurological sequelae. Key disorders include MTHFR deficiency (homocystinuria, developmental delay), hereditary folate malabsorption (SLC46A1 mutations; megaloblastic anemia, immunodeficiency), and cerebral folate deficiency (FOLR1 mutations; psychomotor regression, seizures). Biochemical hallmarks include low serum/CSF folate, hyperhomocysteinemia, and megaloblastic anemia. Early intervention with folinic acid, betaine, or intramuscular folate is critical to mitigate irreversible neurological damage [1][4][7][9].
Population
Rare, with ~60 reported hereditary folate malabsorption cases [7][9], <20 cerebral folate deficiency cases [2], and variable MTHFR deficiency prevalence (common 677C>T polymorphism affects ~10% globally [5]).
Neonates/infants typically affected, though adult-onset cases (e.g., cblG/cblE disorders) mimic neuropsychiatric conditions [1][15].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
101 drug discovery papers about Disorder of folate metabolism and transport, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
101 drug discovery papers about Disorder of folate metabolism and transport, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-18 | Remarkable Clinical Improvement After Folinic Acid Supplementation in Cerebral Folate Transport Deficiency and Epileptic Encephalopathy: A Case Report
Introduction: Folate plays a critical role in central nervous system development, particularly in myelin synthesis and neurotransmitter metabolism. Cerebral folate transport deficiency (CFTD), most often caused by biallelic pathogenic variants in the FOLR1 gene, results in markedly reduced cerebrospinal fluid (CSF) folate levels despite normal systemic folate status. Affected individuals typically present with developmental regression, seizures, and movement disorders. Early diagnosis and folinic acid supplementation have been shown to reverse neurological symptoms, emphasizing the importance of prompt recognition. Case Presentation: We describe a 6-year-old girl born to consanguineous parents who initially presented with autism spectrum disorder and drug-resistant epilepsy. Her seizures included myoclonic–atonic, generalized myoclonic, and focal seizures, with subsequent gait instability and ataxia. Neuroimaging revealed diffuse cerebral atrophy and white matter signal abnormalities. Subsequent genetic testing identified a homozygous FOLR1 missense likely pathogenic variant (c.544T>A; p.Phe182Ile). The diagnosis was further confirmed by CSF analysis showing severe folate deficiency (5-MTHF: 4 nmol/L). Following initiation of oral folinic acid (4 mg/kg/day), seizures resolved completely, and substantial improvements were observed in ambulation, speech, and social interaction. Conclusion: This case illustrates that folinic acid supplementation can lead to remarkable neurological recovery, even with substantial diagnostic delay. FOLR1-related CFTD should be considered in children with refractory epilepsy and developmental regression
2026-04-23 | Dolutegravir developmental toxicity is mitigated by magnesium and folate in zebrafish embryos.
Integrase strand transfer inhibitors have transformed human immunodeficiency virus (HIV) therapy, yet the widely prescribed drug dolutegravir (DTG) has been linked to developmental toxicity, and its teratogenic mechanism remains unclear. Here, we used zebrafish to dissect DTG toxicity during early vertebrate development. DTG exposure from 2-4 h post-fertilization (hpf) to 24 hpf produced high mortality and abnormal morphology. Co-treatment with folates partially restored normal morphology, whereas calcium had no effect. Strikingly, supplementation with magnesium (Mg) partially rescued DTG-exposed embryos, implicating Mg availability in protection. In competitive binding assays, Mg increased binding of folate to purified folate receptor (FOLR1) by 30% in the presence of DTG. folr1 mutant embryos contained significantly less endogenous folate than wild-type embryos and displayed marked hypersensitivity to DTG that could not be mitigated by folate supplementation. Critically, Mg supplementation partially rescued DTG toxicity in folr1 mutants, indicating a Folr1-independent component and placing the balance between free DTG and Mg-bound DTG upstream of folate transport. These results support a model in which free DTG antagonizes FOLR1 and Mg modifies DTG developmental toxicity through FOLR1-dependent and -independent processes.
2026-04-17 | Proteome-wide reverse molecular docking reveals folate receptor as a mediator of PFAS-induced neurodevelopmental toxicity.
Per- and polyfluoroalkyl substances (PFAS) are a class of long-lasting chemicals with widespread use and environmental persistence that have been increasingly studied for their detrimental impacts on human and animal health. Several major PFAS species are linked to neurodevelopmental toxicity. For example, epidemiological studies have associated prenatal exposure to perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) with autism risk. However, the neurodevelopmental toxicities of major PFAS species have not been systematically evaluated in an animal model, and the molecular mechanisms underlying these toxicities have remained elusive. Using a high-throughput zebrafish social behavioral model, we screened six major PFAS species currently under regulation by the Environmental Protection Agency (EPA), including PFOA, PFNA, perfluorooctane sulfonate (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorobutane sulfonate (PFBS), and hexafluoropropylene oxide dimer acid ammonium salt (GenX). We found that embryonic exposure to PFNA, PFOA, and PFOS induced social deficits in zebrafish, recapitulating one of the hallmark behavioral deficits in autistic individuals. To systematically identify potential molecular targets of PFAS, we applied a proteome-wide reverse molecular docking strategy that screens small molecules against predicted binding pockets across the human structural proteome. Using this approach, we screened a virtual library containing predicted binding pockets of over 80% of the 3D human proteome. The screen predicts that folate receptor beta (FR-β, encoded by the gene FOLR2) interacts strongly with PFNA, PFOA, and PFOS but to a lesser degree with PFHxS, PFBS, and GenX, correlating positively with their in vivo toxicity. These predictions were validated through in silico molecular docking, in vitro protein binding analysis, and in vivo targeted metabolomics and loss-of-function verifications. Furthermore, embryonic co-exposure to folic acid effectively rescued social deficits induced by PFAS. Together, these results demonstrate the utility of proteome-wide reverse docking as a powerful strategy for discovering molecular targets of environmental toxicants and identify the folate pathway as a potential mechanism underlying PFAS-induced neurodevelopmental toxicity.
2026-02-04 | Folate receptor 1 activation suppresses high glucose-induced amyloidogenesis in neurons via STAT3/Nrf2 pathway-dependent mitigation of mitochondrial oxidative stress.
Diabetes is a major risk factor for diabetic encephalopathy (DE), which is closely associated with sporadic Alzheimer's disease. Folic acid (FA) receptor signaling can suppress generation of neuropathogenic amyloid-beta (Aβ) induced by high extracellular glucose, suggesting that enhanced activation of this pathway could be a therapeutic strategy against DE-associated dementia, but the precise molecular signaling mechanisms are unclear. We report that high glucose levels increased the expression of amyloid precursor protein (APP) and β-secretase (BACE1) in cultured neurons and concomitantly induced amyloidogenesis, while FA treatment suppressed high glucose-stimulated expression of APP and BACE1, Aβ release, and accumulation of mitochondrial reactive oxygen species. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was minimal under high glucose conditions, but was significantly upregulated together with downstream antioxidant enzymes following FA co-treatment. High glucose stimulation also increased folate receptor 1 (FOLR1) mRNA expression, suggesting a compensatory protective response. While treatment with 5-methyltetrahydrofolate (5-MTHF), the activated form of folate, did not significantly alter high glucose-induced upregulation of APP and BACE1, knockdown of FOLR1 mRNA reduced high glucose-stimulated Nrf2 expression and further augmented APP and BACE1 expression under high glucose conditions. Treatment with the STAT3 inhibitor 5'15-DPP also abolished high glucose-stimulated Nrf2 expression and increased APP and BACE1 expression levels. These findings indicate that FA/FOLR1 activation suppresses high glucose-induced amyloidogenesis by mitigating mitochondrial oxidative stress via STAT3/Nrf2 pathway signaling. In conclusion, present study suggests that the FA/FOLR1/STAT3/Nrf2 pathway is an effective therapeutic target for DE.
2025-11-24 | Comparative Analysis of Treatment With Folate Forms in Clinical Practice.
Folate compounds are crucial for DNA and RNA synthesis, homocysteine regulation, and epigenetic methylation. However, significant differences exist between 5-methyltetrahydrofolate (5-MTHF) and folinic acid (CHO-THF) -and synthetic folic acid (sFA). Understanding their absorption, bioavailability, and clinical effects is essential, especially for women planning pregnancy, pregnant women, and patients with MTHFR or DHFR polymorphisms, autism spectrum disorders, or other folate-related conditions. A comparative analysis of clinical and biochemical studies was conducted to evaluate the efficacy, safety, and optimal dosing of these folate forms. 5-MTHF and CHO-THF demonstrated key advantages over sFA, including avoidance of unmetabolized folic acid accumulation, reduced risk of masking vitamin B12 deficiency, and improved metabolic support in individuals with genetic variants or folate receptor dysfunction. Both forms also show enhanced activity in high-dose therapies for patients with autoantibodies to folate receptors or transport defects. 5-MTHF efficiently crosses the blood-brain barrier, supports fetal and neonatal brain development, and has shown potential in improving cognitive function and depressive symptoms. CHO-THF exhibits promise in managing autism spectrum disorders by modulating neurotransmission and neurometabolic pathways. Despite these advantages, sFA remains the only folate form with proven efficacy in large randomized clinical trials for preventing neural tube defects (NTDs) and continues to play a key role in public health strategies. Use of sFA at doses above 1000 µg/day requires monitoring to avoid masking B12 deficiency. For personalized or high-risk cases, 5-MTHF and CHO-THF should be the preferred options, ideally combined with vitamin B12 supplementation.
gene therapies
2022-01-26 | Arabidopsis non-host resistance PSS30 gene enhances broad-spectrum disease resistance in the soybean cultivar Williams 82.
Non-host resistance (NHR), which protects all members of a plant species from non-adapted or non-host plant pathogens, is the most common form of plant immunity. NHR provides the most durable and robust form of broad-spectrum immunity against non-adaptive pathogens pathogenic to other crop species. In a mutant screen for loss of Arabidopsis (Arabidopsis thaliana) NHR against the soybean (Glycine max (L.) Merr.) pathogen Phytophthora sojae, the Phytophthora sojae-susceptible 30 (pss30) mutant was identified. The pss30 mutant is also susceptible to the soybean pathogen Fusarium virguliforme. PSS30 encodes a folate transporter, AtFOLT1, which was previously localized to chloroplasts and implicated in the transport of folate from the cytosol to plastids. We show that two Arabidopsis folate biosynthesis mutants with reduced folate levels exhibit a loss of non-host immunity against P. sojae. As compared to the wild-type Col-0 ecotype, the steady-state folate levels are reduced in the pss1, atfolt1 and two folate biosynthesis mutants, suggesting that folate is required for non-host immunity. Overexpression of AtFOLT1 enhances immunity of transgenic soybean lines against two serious soybean pathogens, the fungal pathogen F. virguliforme and the soybean cyst nematode (SCN) Heterodera glycines. Transgenic lines showing enhanced SCN resistance also showed increased levels of folate accumulation. This study thus suggests that folate contributes to non-host plant immunity and that overexpression of a non-host resistance gene could be a suitable strategy for generating broad-spectrum disease resistance in crop plants.
2006-12-22 | Micronutrient and urate transport in choroid plexus and kidney: implications for drug therapy.
With application of molecular biology techniques, there has been rapid progress in understanding how many drugs and micronutrients (e.g., vitamins) are transferred across the choroid plexus (CP), the main transport locus of the blood-cerebrospinal fluid (CSF) barrier, and the renal tubular epithelial cells. In many cases, these molecules are transported by separate, specific carriers or receptors on the apical and/or basal side of the CP or renal epithelial cells. This commentary focuses on four micronutrient transport systems in CP (ascorbic acid, folate, inositol, and riboflavin), all of which have been recently cloned, expressed and for which knockout mice models were developed and transporter localization studies performed. Also reviewed is the recently cloned uric acid transport system in human kidney in which there exists a human "knockout" model. The implications of these transport systems for drug therapy of central nervous system and renal disorders are discussed, especially with regard to methods to circumvent the blood-brain and blood-CSF barriers to deliver drugs to the brain.
antibodies
2024-10-06 | Characterizing the genomic landscape through the lens of FOLR1 status in low and high grade serous ovarian carcinoma.
Targeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HGSOC) is now a mainstay for platinum-resistant disease. However, the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LGSOC) is not well documented. Less common than HGSOC, LGSOC tends to respond poorly to traditional platinum-based chemotherapeutic regimens, particularly in recurrence. Thus, there is an urgent need to identify molecular targets that may assist in identifying more efficacious treatments for LGSOC. In this work, we assessed the genomic and transcriptomic landscapes in FOLR1-positive/negative LGSOC compared to its high-grade counterpart. Using a large precision oncology database, next-generation sequencing and immunohistochemistry was performed on a cohort of 281 LGSOC and 5086 HGSOC. Associated MAPK activation was calculated based on NGS results and patient survival analysis was completed stratified by molecular alteration. Compared with LGSOC (24.6 %), HGSOC tumors have significantly higher prevalence of FOLR1+ status (43.5 %) and significantly higher PD-L1+ status. Conversely, LGSOC had higher prevalence of KRAS and NRAS mutations, with a near exclusivity for BRAF mutation compared to HGSOC. FOLR1- LGSOC and HGSOC had similar prevalences of T cell-inflamed tumors, though FOLR1+ LGSOC had a significantly lower prevalence of T-Cell inflamed tumors than FOLR1+ HGSOC. MAPK activation, quantified via MAPK activation score (MPAS), was significantly higher in low-grade tumors compared to HGSOC, yet no difference between FOLR1+ vs FOLR1- LGSOC was observed. Though less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.
2013-04-01 | Nuclear localization of folate receptor alpha: a new role as a transcription factor.
Folic acid (FA) has traditionally been associated with prevention of neural tube defects; more recent work suggests that it may also be involved in in the prevention of adult onset diseases. As the role of FA in human health and disease expands, it also becomes more critical to understand the mechanisms behind FA action. In this work we examined the hypothesis that folate receptor alpha (FRα) acts as a transcription factor. FRα is a GPI-anchored protein and a component of the caveolae fraction. The work described here shows that FRα translocates to the nucleus, where it binds to cis-regulatory elements at promoter regions of Fgfr4 and Hes1, and regulates their expression. The FRα recognition domain mapped to AT rich regions on the promoters. Until this time FRα has only been considered as a folate transporter, these studies describe a novel role for FRα as a transcription factor.
proteins
2025-02-10 | Mechanistic insights into mutation in the proton-coupled folate transporter (SLC46A1) causing hereditary folate malabsorption.
Hereditary folate malabsorption (HFM) is a rare, autosomal recessive disorder characterized by impaired intestinal absorption and impaired transport of folates across the choroid plexus into cerebral spinal fluid due to inactivating mutations in the human proton-coupled folate transporter (hPCFT) gene, which encodes the proton-coupled folate transporter (PCFT) SLC46A1. Understanding the structural impact of these mutations is crucial for elucidating the mechanistic basis for PCFT function and the pathophysiology of HFM. Recently, the cryo-electron microscopic structural characterization of the Gallus gallus PCFT was obtained, which shares significant sequence identity with hPCFT. We conducted molecular dynamics simulations of hPCFT based on this structure, to explore structural changes induced by functionally defective disease-causing and other mutant proteins and mutations that restore function. Simulations revealed that the mutually mechanistic basis for the loss of function is partial loss of structural integrity of hPCFT primarily manifested in an enlarged and distorted pore accompanied by loss of long-range contacts, less stable, fluctuating inner helices with reduced solvent accessibility, and a marked loss of ordered secondary structures. These changes are reversed by the introduction of compensatory mutations. These findings provide novel insights into the structural and functional consequences of PCFT mutations associated with HFM and provide correlations with kinetic and biochemical properties of the mutant proteins.
2020-01-07 | Substitutions that lock and unlock the proton-coupled folate transporter (PCFT-SLC46A1) in an inward-open conformation.
The proton-coupled folate transporter (PCFT) mediates intestinal absorption of folates and their transport from blood to cerebrospinal fluid across the choroid plexus. Substitutions at Asp-109 in the first intracellular loop between the first and second transmembrane domains (TMDs) abolish PCFT function, but protein expression and trafficking to the cell membrane are retained. Here, we used site-directed mutagenesis, the substituted-cysteine accessibility method, functional analyses, and homology modeling to determine whether the D109A substitution locks PCFT in one of its conformational states. Cys-substituted residues lining the PCFT aqueous translocation pathway and accessible in WT PCFT to the membrane-impermeable cysteine-biotinylation reagent, MTSEA-biotin, lost accessibility when introduced into the D109A scaffold. Substitutions at Gly-305 located exofacially within the eighth TMD, particularly with bulky residues, when introduced into the D109A scaffold largely restored function and MTSEA-biotin accessibility to Cys-substituted residues within the pathway. Likewise, Ser-196 substitution in the fifth TMD, predicted by homology modeling to be in proximity to Gly-305, also partially restored function found in solute transporters, is critical to oscillation of the carrier among its conformational states. Substitutions at Asp-109 and Gly-112 lock PCFT in an inward-open conformation, resulting in the loss of function. However, the integrity of the locked protein is preserved, indicated by the restoration of function after insertion of a second "unlocking" mutation. and accessibility. Similarly, the inactivating G112K substitution within the first intracellular loop was partially reactivated by introducing the G305L substitution. These data indicate that the first intracellular loop, with a sequence identical to "motif A" (GXXXDXXGR(R/K)).
small molecules
2026-06-18 | Remarkable Clinical Improvement After Folinic Acid Supplementation in Cerebral Folate Transport Deficiency and Epileptic Encephalopathy: A Case Report
Introduction: Folate plays a critical role in central nervous system development, particularly in myelin synthesis and neurotransmitter metabolism. Cerebral folate transport deficiency (CFTD), most often caused by biallelic pathogenic variants in the FOLR1 gene, results in markedly reduced cerebrospinal fluid (CSF) folate levels despite normal systemic folate status. Affected individuals typically present with developmental regression, seizures, and movement disorders. Early diagnosis and folinic acid supplementation have been shown to reverse neurological symptoms, emphasizing the importance of prompt recognition. Case Presentation: We describe a 6-year-old girl born to consanguineous parents who initially presented with autism spectrum disorder and drug-resistant epilepsy. Her seizures included myoclonic–atonic, generalized myoclonic, and focal seizures, with subsequent gait instability and ataxia. Neuroimaging revealed diffuse cerebral atrophy and white matter signal abnormalities. Subsequent genetic testing identified a homozygous FOLR1 missense likely pathogenic variant (c.544T>A; p.Phe182Ile). The diagnosis was further confirmed by CSF analysis showing severe folate deficiency (5-MTHF: 4 nmol/L). Following initiation of oral folinic acid (4 mg/kg/day), seizures resolved completely, and substantial improvements were observed in ambulation, speech, and social interaction. Conclusion: This case illustrates that folinic acid supplementation can lead to remarkable neurological recovery, even with substantial diagnostic delay. FOLR1-related CFTD should be considered in children with refractory epilepsy and developmental regression
2026-04-23 | Dolutegravir developmental toxicity is mitigated by magnesium and folate in zebrafish embryos.
Integrase strand transfer inhibitors have transformed human immunodeficiency virus (HIV) therapy, yet the widely prescribed drug dolutegravir (DTG) has been linked to developmental toxicity, and its teratogenic mechanism remains unclear. Here, we used zebrafish to dissect DTG toxicity during early vertebrate development. DTG exposure from 2-4 h post-fertilization (hpf) to 24 hpf produced high mortality and abnormal morphology. Co-treatment with folates partially restored normal morphology, whereas calcium had no effect. Strikingly, supplementation with magnesium (Mg) partially rescued DTG-exposed embryos, implicating Mg availability in protection. In competitive binding assays, Mg increased binding of folate to purified folate receptor (FOLR1) by 30% in the presence of DTG. folr1 mutant embryos contained significantly less endogenous folate than wild-type embryos and displayed marked hypersensitivity to DTG that could not be mitigated by folate supplementation. Critically, Mg supplementation partially rescued DTG toxicity in folr1 mutants, indicating a Folr1-independent component and placing the balance between free DTG and Mg-bound DTG upstream of folate transport. These results support a model in which free DTG antagonizes FOLR1 and Mg modifies DTG developmental toxicity through FOLR1-dependent and -independent processes.
2026-04-17 | Proteome-wide reverse molecular docking reveals folate receptor as a mediator of PFAS-induced neurodevelopmental toxicity.
Per- and polyfluoroalkyl substances (PFAS) are a class of long-lasting chemicals with widespread use and environmental persistence that have been increasingly studied for their detrimental impacts on human and animal health. Several major PFAS species are linked to neurodevelopmental toxicity. For example, epidemiological studies have associated prenatal exposure to perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) with autism risk. However, the neurodevelopmental toxicities of major PFAS species have not been systematically evaluated in an animal model, and the molecular mechanisms underlying these toxicities have remained elusive. Using a high-throughput zebrafish social behavioral model, we screened six major PFAS species currently under regulation by the Environmental Protection Agency (EPA), including PFOA, PFNA, perfluorooctane sulfonate (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorobutane sulfonate (PFBS), and hexafluoropropylene oxide dimer acid ammonium salt (GenX). We found that embryonic exposure to PFNA, PFOA, and PFOS induced social deficits in zebrafish, recapitulating one of the hallmark behavioral deficits in autistic individuals. To systematically identify potential molecular targets of PFAS, we applied a proteome-wide reverse molecular docking strategy that screens small molecules against predicted binding pockets across the human structural proteome. Using this approach, we screened a virtual library containing predicted binding pockets of over 80% of the 3D human proteome. The screen predicts that folate receptor beta (FR-β, encoded by the gene FOLR2) interacts strongly with PFNA, PFOA, and PFOS but to a lesser degree with PFHxS, PFBS, and GenX, correlating positively with their in vivo toxicity. These predictions were validated through in silico molecular docking, in vitro protein binding analysis, and in vivo targeted metabolomics and loss-of-function verifications. Furthermore, embryonic co-exposure to folic acid effectively rescued social deficits induced by PFAS. Together, these results demonstrate the utility of proteome-wide reverse docking as a powerful strategy for discovering molecular targets of environmental toxicants and identify the folate pathway as a potential mechanism underlying PFAS-induced neurodevelopmental toxicity.
2026-02-04 | Folate receptor 1 activation suppresses high glucose-induced amyloidogenesis in neurons via STAT3/Nrf2 pathway-dependent mitigation of mitochondrial oxidative stress.
Diabetes is a major risk factor for diabetic encephalopathy (DE), which is closely associated with sporadic Alzheimer's disease. Folic acid (FA) receptor signaling can suppress generation of neuropathogenic amyloid-beta (Aβ) induced by high extracellular glucose, suggesting that enhanced activation of this pathway could be a therapeutic strategy against DE-associated dementia, but the precise molecular signaling mechanisms are unclear. We report that high glucose levels increased the expression of amyloid precursor protein (APP) and β-secretase (BACE1) in cultured neurons and concomitantly induced amyloidogenesis, while FA treatment suppressed high glucose-stimulated expression of APP and BACE1, Aβ release, and accumulation of mitochondrial reactive oxygen species. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was minimal under high glucose conditions, but was significantly upregulated together with downstream antioxidant enzymes following FA co-treatment. High glucose stimulation also increased folate receptor 1 (FOLR1) mRNA expression, suggesting a compensatory protective response. While treatment with 5-methyltetrahydrofolate (5-MTHF), the activated form of folate, did not significantly alter high glucose-induced upregulation of APP and BACE1, knockdown of FOLR1 mRNA reduced high glucose-stimulated Nrf2 expression and further augmented APP and BACE1 expression under high glucose conditions. Treatment with the STAT3 inhibitor 5'15-DPP also abolished high glucose-stimulated Nrf2 expression and increased APP and BACE1 expression levels. These findings indicate that FA/FOLR1 activation suppresses high glucose-induced amyloidogenesis by mitigating mitochondrial oxidative stress via STAT3/Nrf2 pathway signaling. In conclusion, present study suggests that the FA/FOLR1/STAT3/Nrf2 pathway is an effective therapeutic target for DE.
2025-11-24 | Comparative Analysis of Treatment With Folate Forms in Clinical Practice.
Folate compounds are crucial for DNA and RNA synthesis, homocysteine regulation, and epigenetic methylation. However, significant differences exist between 5-methyltetrahydrofolate (5-MTHF) and folinic acid (CHO-THF) -and synthetic folic acid (sFA). Understanding their absorption, bioavailability, and clinical effects is essential, especially for women planning pregnancy, pregnant women, and patients with MTHFR or DHFR polymorphisms, autism spectrum disorders, or other folate-related conditions. A comparative analysis of clinical and biochemical studies was conducted to evaluate the efficacy, safety, and optimal dosing of these folate forms. 5-MTHF and CHO-THF demonstrated key advantages over sFA, including avoidance of unmetabolized folic acid accumulation, reduced risk of masking vitamin B12 deficiency, and improved metabolic support in individuals with genetic variants or folate receptor dysfunction. Both forms also show enhanced activity in high-dose therapies for patients with autoantibodies to folate receptors or transport defects. 5-MTHF efficiently crosses the blood-brain barrier, supports fetal and neonatal brain development, and has shown potential in improving cognitive function and depressive symptoms. CHO-THF exhibits promise in managing autism spectrum disorders by modulating neurotransmission and neurometabolic pathways. Despite these advantages, sFA remains the only folate form with proven efficacy in large randomized clinical trials for preventing neural tube defects (NTDs) and continues to play a key role in public health strategies. Use of sFA at doses above 1000 µg/day requires monitoring to avoid masking B12 deficiency. For personalized or high-risk cases, 5-MTHF and CHO-THF should be the preferred options, ideally combined with vitamin B12 supplementation.
gene therapies
2022-01-26 | Arabidopsis non-host resistance PSS30 gene enhances broad-spectrum disease resistance in the soybean cultivar Williams 82.
Non-host resistance (NHR), which protects all members of a plant species from non-adapted or non-host plant pathogens, is the most common form of plant immunity. NHR provides the most durable and robust form of broad-spectrum immunity against non-adaptive pathogens pathogenic to other crop species. In a mutant screen for loss of Arabidopsis (Arabidopsis thaliana) NHR against the soybean (Glycine max (L.) Merr.) pathogen Phytophthora sojae, the Phytophthora sojae-susceptible 30 (pss30) mutant was identified. The pss30 mutant is also susceptible to the soybean pathogen Fusarium virguliforme. PSS30 encodes a folate transporter, AtFOLT1, which was previously localized to chloroplasts and implicated in the transport of folate from the cytosol to plastids. We show that two Arabidopsis folate biosynthesis mutants with reduced folate levels exhibit a loss of non-host immunity against P. sojae. As compared to the wild-type Col-0 ecotype, the steady-state folate levels are reduced in the pss1, atfolt1 and two folate biosynthesis mutants, suggesting that folate is required for non-host immunity. Overexpression of AtFOLT1 enhances immunity of transgenic soybean lines against two serious soybean pathogens, the fungal pathogen F. virguliforme and the soybean cyst nematode (SCN) Heterodera glycines. Transgenic lines showing enhanced SCN resistance also showed increased levels of folate accumulation. This study thus suggests that folate contributes to non-host plant immunity and that overexpression of a non-host resistance gene could be a suitable strategy for generating broad-spectrum disease resistance in crop plants.
2006-12-22 | Micronutrient and urate transport in choroid plexus and kidney: implications for drug therapy.
With application of molecular biology techniques, there has been rapid progress in understanding how many drugs and micronutrients (e.g., vitamins) are transferred across the choroid plexus (CP), the main transport locus of the blood-cerebrospinal fluid (CSF) barrier, and the renal tubular epithelial cells. In many cases, these molecules are transported by separate, specific carriers or receptors on the apical and/or basal side of the CP or renal epithelial cells. This commentary focuses on four micronutrient transport systems in CP (ascorbic acid, folate, inositol, and riboflavin), all of which have been recently cloned, expressed and for which knockout mice models were developed and transporter localization studies performed. Also reviewed is the recently cloned uric acid transport system in human kidney in which there exists a human "knockout" model. The implications of these transport systems for drug therapy of central nervous system and renal disorders are discussed, especially with regard to methods to circumvent the blood-brain and blood-CSF barriers to deliver drugs to the brain.
antibodies
2024-10-06 | Characterizing the genomic landscape through the lens of FOLR1 status in low and high grade serous ovarian carcinoma.
Targeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HGSOC) is now a mainstay for platinum-resistant disease. However, the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LGSOC) is not well documented. Less common than HGSOC, LGSOC tends to respond poorly to traditional platinum-based chemotherapeutic regimens, particularly in recurrence. Thus, there is an urgent need to identify molecular targets that may assist in identifying more efficacious treatments for LGSOC. In this work, we assessed the genomic and transcriptomic landscapes in FOLR1-positive/negative LGSOC compared to its high-grade counterpart. Using a large precision oncology database, next-generation sequencing and immunohistochemistry was performed on a cohort of 281 LGSOC and 5086 HGSOC. Associated MAPK activation was calculated based on NGS results and patient survival analysis was completed stratified by molecular alteration. Compared with LGSOC (24.6 %), HGSOC tumors have significantly higher prevalence of FOLR1+ status (43.5 %) and significantly higher PD-L1+ status. Conversely, LGSOC had higher prevalence of KRAS and NRAS mutations, with a near exclusivity for BRAF mutation compared to HGSOC. FOLR1- LGSOC and HGSOC had similar prevalences of T cell-inflamed tumors, though FOLR1+ LGSOC had a significantly lower prevalence of T-Cell inflamed tumors than FOLR1+ HGSOC. MAPK activation, quantified via MAPK activation score (MPAS), was significantly higher in low-grade tumors compared to HGSOC, yet no difference between FOLR1+ vs FOLR1- LGSOC was observed. Though less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.
2013-04-01 | Nuclear localization of folate receptor alpha: a new role as a transcription factor.
Folic acid (FA) has traditionally been associated with prevention of neural tube defects; more recent work suggests that it may also be involved in in the prevention of adult onset diseases. As the role of FA in human health and disease expands, it also becomes more critical to understand the mechanisms behind FA action. In this work we examined the hypothesis that folate receptor alpha (FRα) acts as a transcription factor. FRα is a GPI-anchored protein and a component of the caveolae fraction. The work described here shows that FRα translocates to the nucleus, where it binds to cis-regulatory elements at promoter regions of Fgfr4 and Hes1, and regulates their expression. The FRα recognition domain mapped to AT rich regions on the promoters. Until this time FRα has only been considered as a folate transporter, these studies describe a novel role for FRα as a transcription factor.
proteins
2025-02-10 | Mechanistic insights into mutation in the proton-coupled folate transporter (SLC46A1) causing hereditary folate malabsorption.
Hereditary folate malabsorption (HFM) is a rare, autosomal recessive disorder characterized by impaired intestinal absorption and impaired transport of folates across the choroid plexus into cerebral spinal fluid due to inactivating mutations in the human proton-coupled folate transporter (hPCFT) gene, which encodes the proton-coupled folate transporter (PCFT) SLC46A1. Understanding the structural impact of these mutations is crucial for elucidating the mechanistic basis for PCFT function and the pathophysiology of HFM. Recently, the cryo-electron microscopic structural characterization of the Gallus gallus PCFT was obtained, which shares significant sequence identity with hPCFT. We conducted molecular dynamics simulations of hPCFT based on this structure, to explore structural changes induced by functionally defective disease-causing and other mutant proteins and mutations that restore function. Simulations revealed that the mutually mechanistic basis for the loss of function is partial loss of structural integrity of hPCFT primarily manifested in an enlarged and distorted pore accompanied by loss of long-range contacts, less stable, fluctuating inner helices with reduced solvent accessibility, and a marked loss of ordered secondary structures. These changes are reversed by the introduction of compensatory mutations. These findings provide novel insights into the structural and functional consequences of PCFT mutations associated with HFM and provide correlations with kinetic and biochemical properties of the mutant proteins.
2020-01-07 | Substitutions that lock and unlock the proton-coupled folate transporter (PCFT-SLC46A1) in an inward-open conformation.
The proton-coupled folate transporter (PCFT) mediates intestinal absorption of folates and their transport from blood to cerebrospinal fluid across the choroid plexus. Substitutions at Asp-109 in the first intracellular loop between the first and second transmembrane domains (TMDs) abolish PCFT function, but protein expression and trafficking to the cell membrane are retained. Here, we used site-directed mutagenesis, the substituted-cysteine accessibility method, functional analyses, and homology modeling to determine whether the D109A substitution locks PCFT in one of its conformational states. Cys-substituted residues lining the PCFT aqueous translocation pathway and accessible in WT PCFT to the membrane-impermeable cysteine-biotinylation reagent, MTSEA-biotin, lost accessibility when introduced into the D109A scaffold. Substitutions at Gly-305 located exofacially within the eighth TMD, particularly with bulky residues, when introduced into the D109A scaffold largely restored function and MTSEA-biotin accessibility to Cys-substituted residues within the pathway. Likewise, Ser-196 substitution in the fifth TMD, predicted by homology modeling to be in proximity to Gly-305, also partially restored function found in solute transporters, is critical to oscillation of the carrier among its conformational states. Substitutions at Asp-109 and Gly-112 lock PCFT in an inward-open conformation, resulting in the loss of function. However, the integrity of the locked protein is preserved, indicated by the restoration of function after insertion of a second "unlocking" mutation. and accessibility. Similarly, the inactivating G112K substitution within the first intracellular loop was partially reactivated by introducing the G305L substitution. These data indicate that the first intracellular loop, with a sequence identical to "motif A" (GXXXDXXGR(R/K)).
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