RESUMEN
Folate deficiencies, folate imbalance and associated abnormal methylation are associated with birth defects, developmental delays, neurological conditions and diseases. In the hydrocephalic Texas (H-Tx) rat, 10-formyl tetrahydrofolate dehydrogenase (FDH) is reduced or absent from the CSF and the nuclei of cells in the brain and liver and this is correlated with decreased DNA methylation. In the present study, we tested whether impaired folate metabolism or methylation exists in sexually mature, unaffected H-Tx rats, which may explain the propagation of hydrocephalus in their offspring. We compared normal Sprague Dawley (SD, n = 6) rats with untreated H-Tx (uH-Tx, n = 6 and folate-treated H-Tx (TrH-Tx, n = 4). Structural abnormalities were observed in the testis of uH-Tx rats, with decreased methylation, increased demethylation, and cell death, particularly of sperm. FDH and FRα protein expression was increased in uH-Tx males but not in folate-treated males but tissue folate levels were unchanged. 5-Methylcytosine was significantly reduced in untreated and partially restored in treated individuals, while 5-hydroxymethylcytosine was not significantly changed. Similarly, a decrease in DNA-methyltransferase-1 expression in uH-Tx rats was partially reversed with treatment. The data expose a significant germline methylation error in unaffected adult male H-Tx rats from which hydrocephalic offspring are obtained. Reduced methylation in the testis and sperm was partially recovered by treatment with folate supplements leading us to conclude that this neurological disorder may not be completely eradicated by maternal supplementation alone.
Asunto(s)
Ácido Fólico , Hidrocefalia , Animales , Masculino , Ratas , Metilación de ADN , Ácido Fólico/metabolismo , Ácido Fólico/farmacología , Ácido Fólico/uso terapéutico , Ratas Sprague-Dawley , Semen/metabolismo , Hidrocefalia/congénito , Hidrocefalia/tratamiento farmacológico , Hidrocefalia/genética , Hidrocefalia/metabolismo , Modelos Animales de Enfermedad , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismoRESUMEN
Metabolic disorders may be important potential causative pathways to Alzheimer's disease (AD). Cerebrospinal fluid (CSF) decreasing output, raised intracranial pressure, and ventricular enlargement have all been linked to AD. Cerebral folate metabolism may be a key player since this is significantly affected by such changes in CSF, and genetic susceptibilities may exist in this pathway. In the current study, we aimed to identify whether any single nucleotide polymorphism (SNPs) affecting folate and the associated metabolic pathways were significantly associated with AD. We took a functional nutrigenomics approach to look for SNPs in genes for the linked folate, methylation, and biogenic amine neurotransmitter pathways. Changes in metabolism were found with the SNPs identified. An abnormal SNP in methylene tetrahydrofolate dehydrogenase 1 (MTHFD1) was significantly predictive of AD and associated with an increase in tissue glutathione. Individuals without these SNPs had normal levels of glutathione but significantly raised MTHFD1. Both changes would serve to decrease potentially neurotoxic levels of homocysteine. Seven additional genes were associated with Alzheimer's and five with normal ageing. MTHFD1 presents a strong prediction of susceptibility and disease among the SNPs associated with AD. Associated physiological changes present potential biomarkers for identifying at-risk individuals.