Autoantibodies against homocysteinylated protein in a mouse model of folate deficiency-induced neural tube defects

Denny, Kerina J., Kelly, Christina F., Kumar, Vinod, Witham, Katey L., Cabrera, Robert M., Fennell, Richard H., Taylor, Stephen M., Jeanes, Angela and Woodruff, Trent M. (2016) Autoantibodies against homocysteinylated protein in a mouse model of folate deficiency-induced neural tube defects. Birth Defects Research Part A: Clinical and Molecular Teratology, 106 3: 201-207. doi:10.1002/bdra.23483

Author Denny, Kerina J.
Kelly, Christina F.
Kumar, Vinod
Witham, Katey L.
Cabrera, Robert M.
Fennell, Richard H.
Taylor, Stephen M.
Jeanes, Angela
Woodruff, Trent M.
Title Autoantibodies against homocysteinylated protein in a mouse model of folate deficiency-induced neural tube defects
Journal name Birth Defects Research Part A: Clinical and Molecular Teratology   Check publisher's open access policy
ISSN 1542-0752
Publication date 2016-02-22
Sub-type Article (original research)
DOI 10.1002/bdra.23483
Open Access Status Not Open Access
Volume 106
Issue 3
Start page 201
End page 207
Total pages 7
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Collection year 2017
Language eng
Formatted abstract
Background: Periconceptional supplementation with folic acid results in a significant reduction in the incidence of neural tube defects (NTDs). Nonetheless, NTDs remain a leading cause of perinatal morbidity and mortality worldwide, and the mechanism(s) by which folate exerts its protective effects are unknown. Homocysteine is an amino acid that accumulates under conditions of folate-deficiency, and is suggested as a risk factor for NTDs. One proposed mechanism of homocysteine toxicity is its accumulation into proteins in a process termed homocysteinylation.

Methods & Results: Herein, we used a folate-deficient diet in pregnant mice to demonstrate that there is: (i) a significant inverse correlation between maternal serum folate levels and serum homocysteine; (ii) a significant positive correlation between serum homocysteine levels and titers of autoantibodies against homocysteinylated protein; and (iii) a significant increase in congenital malformations and NTDs in mice deficient in serum folate. Furthermore, in mice administered the folate-deplete diet before conception, supplementation with folic acid during the gestational period completely rescued the embryos from congenital defects, and resulted in homocysteinylated protein titers at term that are comparable to that of mice administered a folate-replete diet throughout both the pre- and postconception period. These results demonstrate that a low-folate diet that induces NTDs also increases protein homocysteinylation and the subsequent generation of autoantibodies against homocysteinylated proteins.

Conclusion: These data support the hypotheses that homocysteinylation results in neo-self antigen formation under conditions of maternal folate deficiency, and that this process is reversible with folic acid supplementation. Birth Defects Research (Part A), 2016.
Keyword Autoantibodies
Neural tube defects
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Early view of article

Document type: Journal Article
Sub-type: Article (original research)
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Created: Thu, 03 Mar 2016, 10:47:21 EST by Dr Angela Jeanes on behalf of School of Biomedical Sciences