Protein mutation linked to abnormal brain development

A research team led by the Walter and Eliza Hall Institute (WEHI) has proven that a protein called Trabid helps control neuronal development, and that mutations to this protein can lead to microcephaly — a condition where a baby’s brain is smaller than expected. It is hoped that their findings, published in the journal eLife, will provide a deeper understanding into the protein’s impact on healthy development and lead to treatments that can slow or stop the development of microcephaly and other neurological disorders.

Microcephaly is a neurodevelopmental condition leading to an underdeveloped brain that adversely affects learning and behaviour. In 2015, UK researchers published a study that first suggested a possible connection between the gene encoding Trabid (ZRANB1) and microcephaly, after identifying two patients with the brain disorder who had mutations in this gene. WEHI’s Dr Hoanh Tran, who has over 10 years of experience investigating Trabid, was able to build on this research by characterising these patient mutations in the lab using preclinical models.

Tran’s new study is understood to be the first to show that Trabid plays a critical role in the development of healthy neurons — the fundamental building blocks of the nervous system — by ensuring they are guided correctly in the developing brain, ultimately enabling normal brain function and behaviour. He explained, “Cells in the developing brain must migrate to the right location. If the address is missed, developmental defects can occur.

“Healthy neurons extend long processes called axons in a directional, ordered manner,” Tran continued. “In our study, we found the neurons from models with defective Trabid project axons that migrate with a wayward trajectory.

“These significant findings provide an understanding of Trabid/ZRANB1 as a new human microcephaly gene.”

Currently, microcephaly can sometimes be diagnosed with an ultrasound test during the second or third trimester. The team hopes that defects in Trabid, or the proteins that Trabid controls, could in future be used to help identify babies who are at risk of developing microcephaly, allowing for potential early interventions.

Image shows neurons and their connections to each other in red and yellow, and the cell’s DNA in blue. Image credit: Simone Seizova and Shiraz Tyebji, WEHI.