Protein Aggregation Implicated in Neural Tube Defects

Misfolded proteins related to neurodegenerative diseases can lead to neural tube defects.

Maternal food and medication intake during pregnancy, along with other outside factors, can be helpful or harmful to a developing fetus. A new study published by Proceedings of the National Academy of Sciences found evidence that neurological birth defects are linked to maternal diabetes and neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

The authors report that this is the first time this link has been found, and the new understandings could be used to improve treatment of neural tube defects among infants whose mother have certain diseases.

"These results were really surprising," said the study's lead author, Zhiyong Zhao, PhD. "The association suggests that these disparate diseases may have more in common than we previously realized."

Neural tube defects refer to birth defects of the brain and spinal cord, which include spina bifida and anencephaly. Spina bifida occurs when the fetal spinal column does not close completely, which typically leads to nerve damage and paralysis.

Anencephaly is characterized by a lack of development of the brain and skull. Fetuses with anencephaly are typically stillborn or die soon after birth, according to the study.

These birth defects occur in approximately 10% of pregnancies, and are caused by diabetes, folic acid deficiency, maternal obesity, and certain medications.

Neural tube defects are the result of misfolded proteins aggregating in the cells of the nervous system of a developing fetus. The misfolded proteins form clumps that lead to widespread cell death and birth defects. Alzheimer’s, Parkinson’s, and Huntington’s diseases are also characterized by protein clumps that reduce organ function.

In the study, the authors studied pregnant mice models of diabetes. They found that the embryos had clumps of at least 3 misfolded proteins linked to the diseases: alpha-Synuclein, Parkin, and Huntington, according to the study. The authors noted that the link between the diseases and the proteins have been well-established, although the underlying reasons are unknown.

The new findings also highlight the link between diabetes and neurodegenerative diseases. Patients with diabetes are at a higher risk of developing Alzheimer’s and Parkinson’s diseases, and other research suggests that there may also be a link to Huntington’s disease.

The authors next examined the possibility of reducing levels of misfolded proteins, therefore, reducing neural tube defects.

Pregnant mice models of diabetes were administered sodium 4-phenylbutyrate (PBA), which is a compound that reduces mistakes by aiding the molecules that monitor correct protein folding, according to the study. The authors discovered that animals treated with PBA had lower rates of misfolded proteins and neural tube defects.

If proven safe and effective in humans, high-risk mothers taking PBA would be less likely to have a child with neural tube defects. Since PBA has been already been approved by the FDA, it could potentially be used as a treatment quickly compared with experimental drugs, the study concluded.