News

The study, published in the journal eLife, is the first to prove 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.

The milestone findings offer hope for a deeper understanding into the protein’s impact on healthy development and for the development of future treatments that could slow or stop the development of microcephaly and potentially other neurological disorders.

At a glance

• World-first study shows how mutations in the Trabid protein can cause microcephaly, an incurable brain disorder.
• The research is the first to uncover Trabid’s critical role in the development of healthy neurons, which are essential for the proper functioning of our nervous system and overall quality of life.  Abnormalities in neuronal development can prevent the brain from developing properly.
• These findings could see Trabid used as a therapeutic target to treat neurodevelopmental disorders in the future.

Microcephaly is a neurodevelopmental condition resulting in an underdeveloped brain that adversely affects learning and behaviour. About 1 in 2,000 babies in Australia are reported to have microcephaly, with no known cure or standard treatment for the disorder.

Neurons, the fundamental building blocks of the nervous system, are instrumental in transmitting electrical and chemical signals that enable communication between different parts of the body and the brain.

The study, led by WEHI in collaboration with the Doherty Institute, is the first to show that Trabid plays a critical role in the development of healthy neurons by ensuring they are guided correctly in the developing brain – ultimately enabling normal brain function and behaviour.

Co-lead author, Associate Professor Grant Dewson, a Laboratory Head at WEHI, said the findings may aid diagnosis and treatment of neurodevelopmental disorders in the future, with 2.5 million Australians believed to be living with one of these conditions.

“Our understanding into how neurodevelopmental conditions, like microcephaly, develop continues to grow,” said Associate Professor Dewson.

“While previous research has indicated there could be a link between defects in Trabid and microcephaly, our study is the first to provide evidence for the gene’s function in neuronal guidance –filling a vital knowledge gap.”

Critical development

In a 2015 study, UK researchers first suggested a possible connection between the Trabid gene (ZRANB1) and microcephaly, after identifying two patients with the brain disorder who had mutations in this gene.

With over 10 years of experience investigating Trabid, University of Melbourne’s Dr Hoanh Tran, joint Laboratory Head and Senior Research Fellow at the Doherty Institute and Senior Research Officer at WEHI, built on this research by characterising these patient mutations in the lab using pre-clinical models.

“Abnormalities in neuron migration and guidance can lead to neurodevelopmental disorders like microcephaly. Cells in the developing brain must migrate to the right location. If the address is missed, developmental defects can occur,” said Dr Tran.

“Healthy neurons extend long processes called axons in a directional, ordered manner. 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.”

University of Melbourne’s Professor Elizabeth Vincan, medical scientist, Laboratory Head at the Doherty Institute, and co-author of the study, said that this research has been a labour of love and dedication.

“Hoanh did not give up as he knew he had something that will lead to improving treatment for rare brain disorders,” said Professor Vincan.

“This is not hype – but solid science where mutations found in children with microencephaly were introduced into a pre-clinical model recapitulating the human condition.

“This type of investment is only possible with long-standing support from labs at WEHI (Professor David Vaux and Associate Professor Grant Dewson) and my lab here at the Doherty Institute.

“Importantly, the mechanisms described form a common theme that is relevant to pathogen entry into cells – very exciting times indeed!” she said.

Therapeutic interventions

Currently, microcephaly can sometimes be diagnosed with an ultrasound test during the second or third trimester of pregnancy.

The team hopes that, in the future, defects in Trabid, or the proteins that Trabid controls, could help identify babies who are at risk of developing microcephaly early – allowing for potential early interventions.

Peer review: Frank D, Bergamasco M, Mlodzianoski M, et al. Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth. eLife (2023). DOI: 10.7554/eLife.90796.3

Funding: The work was supported by the National Health and Medical Research Council (NHMRC), the Bodhi Education Fund, Phenomics Australia, the Australian Government and the Victorian State Government.

Collaboration: The study is the result of collaboration between WEHI, the Doherty Institute and the University of Melbourne.

This news article is based on an original article by WEHI and repurposed with consent.