Neural tube defects commonly found in pregnant women with diabetes may be linked to several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, according to findings published in the early edition of the Proceedings of the National Academy of Sciences.
“These results were really surprising,” said lead author, Zhiyong Zhao, PhD, researcher, University of Maryland School of Medicine (UM SOM), Baltimore, MD. “The association suggests that these disparate diseases may have more in common than we previously realized.”
Neural tube defects are caused by an accumulation of misfolded proteins in cells of the developing nervous system, which form insoluble clumps and associated with Caspase-8-induced programmed cell death, which may lead to birth defects. Such protein clumps also play a role in Parkinson’s, Huntington’s and Alzheimer’s diseases, and in the latter, lead to plaque accumulation and dysfunction of the brain.
Causes of neural tube defects can include diabetes, folic acid deficiency, obesity, and certain medications. Roughly 10% of pregnant mothers with diabetes will have embryos with neural tube defects.
Dr. Zhao and colleagues studied pregnant mice with diabetes, and found that embryos had clumps of at least three misfolded proteins also associated with these three neurodegenerative diseases: α-Synuclein, Parkin, and Huntingtin.
To further study whether these misfolded proteins could be reduced and, consequently, lead to a reduction in neural tube defects, Dr. Zhao and colleagues gave mice sodium 4-phenylbutyrate (PBA), which is a compound that can reduce molecular structure mistakes by helping molecules properly fold proteins. Animals that were treated with PBA had significantly less protein misfolding and fewer neural tube defects in their embryos. They concluded that enhancing protein folding may be a potential interventional approach to preventing embryonic malformations in diabetic pregnancies.
PBA is currently approved by the FDA for urea cycle disorders.