Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

Iskandar, Bermans J.; Rizk, Elias; Meier, Brenton M.; Hariharan, Nithya; Bottiglieri, Teodoro; Finnell, Richard H.; Jarrard, David F.; Banerjee, Ruma; Skene, J. H. Pate; Nelson, Aaron; Patel, Nirav J.; Gherasim, Carmen; Simon, Kathleen; Cook, Thomas D.; Hogan, Kirk

doi:10.1172/jci40000

Cited by 145 publications

(132 citation statements)

References 50 publications

(60 reference statements)

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“…2a). More importantly, and as opposed to a recent study investigating folate and its DNA methylation after sciatic and spinal injury 16 , quantitative RT-PCR analysis of the differentially methylated genes, and DNA methyltransferases did not show a consistent correlation between DNA methylation levels and gene expression (Supplementary Figs 2b-e and 3). Therefore, promoter and CGI DNA methylation does not appear to be a key factor in the differential regenerative response between CNS and PNS injuries in the DRG system.…”

Section: Resultscontrasting

confidence: 87%

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

et al. 2014

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Section: Resultscontrasting

confidence: 87%

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

et al. 2014

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“…Electron microscopy of the brain in these rats showed degenerative changes in the cerebral microvasculature [33]. Furthermore, folate plays an important role in axonal regeneration and repair after induced brain damage in rodent models [34].…”

Section: Animal Models Of the Effects Of Folate Deficiency On Developmentioning

confidence: 90%

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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Autism spectrum disorder (ASD) has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD. Autism spectrum disorder: an emerging disorder with unclear etiology Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 2% of children in the USA [1]. Although it is defined through observation of the presence of abnormal behavior and absence of typical developmental milestones, ASD is associated with a wide range of medical abnormalities such as sleep, immune and gastrointestinal disorders and epilepsy. In addition to medical comorbidities, many children with ASD have disruptions in body physiology such as abnormalities in folate, cobalamin, tetrahydrobiopterin (BH 4 ), neurotransmitter, carnitine, redox and mitochondrial metabolism [2]. The connection between underlying physiological abnormalities and behavior is an area of active research. In this review, we will provide evidence that abnormalities of one-carbon folate metabolism are particularly important in ASD.Although the etiology of ASD is not known, genetics has been the focus of ASD research for many decades [3]. A notion of a pure genetic etiology is tempered by the fact that single gene and chromosomal defects are found in a minority of ASD cases, accounting for only 15.8% of cases when both chromosomal microarray and whole exome sequencing were used in one recent large study [4]. ASD has also been associated with exposures to numerous environmental agents during the prenatal and postnatal period [5]. Studies that have examined the contribution of the environmental and genetic components highlight that ASD arises as a consequence of complicated interactions between genetic predisposition and environmental factors [6,7]. As we will outline in this review, abnormalities in folate metabolism provide an excellent model of how environment factors can interact with genetic predisposition to cause ASD.At this time, the standard of care for ASD treatment is applied behavioral analysis and other equivalent behavioral interventions along with educational, developmental, occupational and speech therapy. Optimal application of behavioral therapy requires full-time one-on-one therapist for many years; however, even when this optimal therapy is applied, suboptimal outcomes are common. In addition, controlled studies examining the efficacy of variou...

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“…The results from this study focus the research field on the neural tissue and the process of neural tube formation as specific targets of folate action and argue for considering more specific roles of the vitamin folate on nervous system development and function. Intriguingly, it has been shown that folate improves axonal regeneration after spinal cord and sciatic nerve injury by an upregulation of Folr1 expression (Iskandar et al, 2010) and supplementation of pregnant rats with a high folate diet alters synaptic transmission and seizure susceptibility in their offspring (Girotto et al, 2013). A recent study shows that the presence of folate receptor-blocking antibodies during gestation and pre-weaning in rats disturbs adult social behavior of offspring (Sequeira et al, 2016), in agreement with the association between folate receptor autoantibodies found in children suffering from the infantile-onset cerebral folate deficiency, who exhibit neuropsychiatric and neurologic manifestations (Ramaekers et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation

2017

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Folate supplementation prevents up to 70% of neural tube defects (NTDs), which result from a failure of neural tube closure during embryogenesis. The elucidation of the mechanisms underlying folate action has been challenging. This study introduces Xenopus laevis as a model to determine the cellular and molecular mechanisms involved in folate action during neural tube formation. We show that knockdown of folate receptor 1 (Folr1; also known as FRα) impairs neural tube formation and leads to NTDs. Folr1 knockdown in neural plate cells only is necessary and sufficient to induce NTDs. Folr1-deficient neural plate cells fail to constrict, resulting in widening of the neural plate midline and defective neural tube closure. Pharmacological inhibition of folate action by methotrexate during neurulation induces NTDs by inhibiting folate interaction with its uptake systems. Our findings support a model in which the folate receptor interacts with cell adhesion molecules, thus regulating the apical cell membrane remodeling and cytoskeletal dynamics necessary for neural plate folding. Further studies in this organism could unveil novel cellular and molecular events mediated by folate and lead to new ways of preventing NTDs.

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Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

Cited by 145 publications

References 50 publications

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation

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